Crystalline forms of an antiviral compound

ABSTRACT

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state: 
                         
Also provided are processes of manufacture and methods of using the crystalline forms.

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/920,427 filed on Dec. 23, 2013, theentirety of which is incorporated herein by reference.

BACKGROUND

The present disclosure relates generally to crystalline forms of theantiviral compound named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide,processes for making the forms, and their therapeutic methods of use.

The hepatitis C virus (HCV), a member of the hepacivirus genera withinthe Flaviviridae family, is the leading cause of chronic liver diseaseworldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently,a significant focus of current antiviral research is directed toward thedevelopment of improved methods for the treatment of chronic HCVinfections in humans (Ciesek, S., von Hahn T., and Manns, M P., Clin.Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob.Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474,S1-S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour,D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

There remains a need to develop effective treatments for HCV infections.Suitable compounds for the treatment of HCV infections are disclosed inU.S. Publication No. 2014-0017198, titled “Inhibitors of Hepatitis CVirus” filed on Jul. 2, 2013 including the compound of formula I:

However, Compound I was not heretofore known in any crystalline form.

SUMMARY

The present disclosure fulfills these needs and others by providingcrystalline forms of Compound I and salts, co-crystals, hydrates andsolvates thereof. The present disclosure also provides pharmaceuticalcompositions comprising crystalline forms of Compound I. The disclosurealso provides processes for making the crystalline forms and methods forusing them in the treatment of HCV.

Thus, one embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethanol solvate (Compound I Form I). Compound I Form I is characterizedby an X-ray powder diffractogram comprising the following peaks (±0.2°):at 8.6, 11.1, and 15.5 °2θ, as determined on a diffractometer usingCu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethyl acetate solvate (Compound I Form II). Compound I Form II ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 8.7, 13.0, and 17.4 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideisopropanol solvate (Compound I Form III). Compound I Form III ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 11.1, 12.8, and 19.7 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedihydrate (Compound I Form IV). Compound I Form IV is characterized byan X-ray powder diffractogram comprising the following peaks (±0.2°): at8.7, 8.9, and 16.0 °2θ as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethanol solvate (Compound I Form V). Compound I Form V is characterizedby an X-ray powder diffractogram comprising the following peaks (±0.2°):at 6.2, 12.4, and 19.6 °2θ, as determined on a diffractometer usingCu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VI). Compound I Form VI is characterized byan X-ray powder diffractogram comprising the following peaks (±0.2°): at14.6, 15.4, and 20.0 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VII). Compound I Form VII is characterizedby an X-ray powder diffractogram comprising the following peaks (±0.2°):at 6.5, 8.5, and 18.7 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VIII). Compound I Form VIII is characterizedby an X-ray powder diffractogram comprising the following peaks (±0.2°):at 7.8, 8.2, and 20.2 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form IX). Compound I Form IX is characterized byan X-ray powder diffractogram comprising the following peaks (±0.2°): at6.1, 9.5, and 19.4 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidehemihydrate (Compound I Form X). Compound I Form X is characterized byan X-ray powder diffractogram comprising the following peaks (±0.2°): at8.0, 19.0, and 20.4 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedihydrate (Compound I Form XI). Compound I Form XI is characterized byan X-ray powder diffractogram comprising the following peaks (±0.2°): at11.0, 13.9, and 20.9 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidetetrahydrate (Compound I Form XII). Compound I Form XII is characterizedby an X-ray powder diffractogram comprising the following peaks (±0.2°):at 12.4, 14.6, and 19.3 °2θ, as determined on a diffractometer usingCu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideisopropyl acetate solvate (Compound I Form XIII). Compound I Form XIIIis characterized by an X-ray powder diffractogram comprising thefollowing peaks (±0.2°): at 8.5, 11.0, and 15.4 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidetetrahydrofuran solvate (Compound I Form XIV). Compound I Form XIV ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 11.2, 15.7, and 17.9 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide2-methyltetrahydrofuran solvate (Compound I Form XV). Compound I Form XVis characterized by an X-ray powder diffractogram comprising thefollowing peaks (±0.2°): at 9.7, 11.0, and 15.5 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidetoluene solvate (Compound I Form XVI). Compound I Form XVI ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 5.8, 7.8, and 18.8 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidetoluene solvate (Compound I Form XVII). Compound I Form XVII ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 7.9, 18.9, and 20.3 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethy test butyl ether solvate (Compound I Form XVIII). Compound I FormXVIII is characterized by an X-ray powder diffractogram comprising thefollowing peaks (±0.2°): at 5.6, 6.4, and 7.5 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethy tert butyl ether solvate (Compound I Form XIX). Compound I FormXIX is characterized by an X-ray powder diffractogram comprising thefollowing peaks (±0.2°): at 11.1, 15.5, and 19.8 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedimethylacetamide solvate (Compound I Form XX). Compound I Form XX ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 11.9, 14.5, and 19.1 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedimethylformamide solvate (Compound I Form XXI). Compound I Form XXI ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 11.7, 12.2, and 14.4 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Some embodiments provided herein relate to crystalline forms of salts orco-crystals of Compound I.

Thus, one embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form I). Compound I sodium Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 5.6, 7.8, and 11.2 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form II). Compound I sodium Form II ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 5.8, 7.3, and 11.1 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form III). Compound I sodium Form III ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 5.4, 7.7, and 10.8 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form IV). Compound I sodium Form IV ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 10.4, 12.1, and 16.6 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemeglumine (Compound I meglumine Form I). Compound I meglumine Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 3.6, 5.1, and 8.9 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepiperazine (Compound I piperazine Form I). Compound I piperazine Form Iis characterized by an X-ray powder diffractogram comprising thefollowing peaks (±0.2°): at 4.9, 7.2, and 8.2 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidecholine (Compound I choline Form I). Compound I choline Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 7.4, 15.5, and 20.9 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedeanol (Compound I deanol Form I). “Deanol” refers todimethylaminoethanol. Compound I deanol Form I is characterized by anX-ray powder diffractogram comprising the following peaks (±0.2°): at7.4, 10.7, and 15.2 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine (HEP) (Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form I). Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form I is characterized by an X-raypowder diffractogram comprising the following peaks (±0.2°): at 8.2,10.8, and 19.9 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine (HEP) (Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form II). Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form II is characterized by anX-ray powder diffractogram comprising the following peaks (±0.2°): at7.7, 8.3, and 15.5 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine (HEP) (Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form III). Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form III is characterized by anX-ray powder diffractogram comprising the following peaks (±0.2°): at7.1, 8.0, and 10.7 °2θ, as determined on a diffractometer using Cu—Kαradiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidelysine (Compound I lysine Form I). Compound I lysine Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 8.2, 10.8, and 19.9 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidearginine (Compound I arginine Form I). Compound I arginine Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 8.2, 10.8, and 19.9 °2θ, as determined on adiffractometer using Cu—Kα radiation.

Another embodiment is directed to crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepotassium (Compound I potassium Form I). Compound I potassium Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks (±0.2°): at 6.4, 8.6, and 15.8 °2θ, as determined on adiffractometer using Cu—Kα radiation.

One embodiment is a composition comprising at least two of Compound IForm I, Compound I Form II, Compound I Form III, Compound I Form IV,Compound I Form V, Compound I Form VI, Compound I Form VII, and CompoundI Form VIII, Compound I Form IX, Compound I Form X, Compound I Form XI,Compound I Form XII, Compound I Form XIII, Compound I Form XIV, CompoundI Form XV, Compound I Form XVI, Compound I Form XVII, Compound I FormXVIII, Compound I Form XIX, Compound I Form XX, and Compound I Form XXI.Additionally, the disclosure provides in one embodiment a method fortreating a subject suffering from hepatitis C virus (HCV). The methodcomprises administering to the subject a therapeutically effectiveamount of any one of Compound I Forms I-XXI, as described generallythroughout.

Still an additional embodiment includes, optionally in combination withany other embodiment described herein, is the use of any one of CompoundI Forms I-XXI and in the manufacture of a medicament for treating HCV ina subject suffering therefrom.

In another embodiment, the disclosure provides a process for makingCompound I Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith ethanol, whereby Compound I Form I is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form II comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith ethyl acetate, whereby Compound I Form II is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form III comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith isopropanol, whereby Compound I Form III is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form IV comprising the step of placing(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethanol solvate (Compound I Form I) at about 40° C. and about 75%relative humidity (R.H.), whereby Compound I Form IV is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form V comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith methanol, whereby Compound I Form V is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form VI comprising the step of heating crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethanol solvate (Compound I Form V) to about 70° C., whereby Compound IForm VI is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form VII comprising the step of heating crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethanol solvate, to about 240° C., whereby Compound I Form VII isformed.

In another embodiment, the disclosure provides a process for makingCompound I Form VIII comprising the steps of

(1) contacting crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VI) with water and heating at about 85° C.in a container; and(2) adding crystalline(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethanol solvate, in a mixture of acetone and water (1:4 by volume) tothe container of step (1) and heating at about 85° C., whereby CompoundI Form VIII is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form IX comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 1:1 heptane/toluene at about 60° C., whereby Compound I Form IX isformed.

In another embodiment, the disclosure provides a process for makingCompound I Form X comprising the steps of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith water and heating to about 80° C., whereby Compound I Form X isformed.

In another embodiment, the disclosure provides a process for makingCompound I Form XI comprising the steps of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith either 1:1, 6:4, or 7:3 (v/v) EtOH:water, whereby Compound I FormXI is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XII comprising the steps of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 4:6 or 1:1 (v/v) EtOH:water and slurring at room temperature, or2:8, 3:7 or 4:6 acetonitrile:water and slurring at room temperature, or2:8, 3:7, 4:6 or 1:1 (v/v) acetone:water and slurring at roomtemperature, whereby Compound I Form XII is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XIII comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith IPAc, whereby Compound I Form XIII is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XIV comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 1:9, 2:8 or 3:7 (v/v) THF:water and slurring at room temperature,whereby Compound I Form XIV is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XV comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 2-Me-THF, whereby Compound I Form XV is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XVI comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 8:2 toluene:heptane, whereby Compound I Form XVI is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XVII comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith toluene, whereby Compound I Form XVII is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XVIII comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith MTBE, whereby Compound I Form XVIII is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XIX comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith 5 volumes of MTBE and 10 volumes of heptane, whereby Compound IForm XIX is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XX comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith DMAc, whereby Compound I Form XX is formed.

In another embodiment, the disclosure provides a process for makingCompound I Form XXI comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidewith DMF, whereby Compound I Form XXI is formed.

In other embodiments, the process of making salts and co-crystals wasperformed by reacting Compound I with a stoichiometric amount of a saltof co-crystal former in a solvent to yield a product.

In another embodiment, the disclosure provides a process for makingCompound I sodium Form I comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium with EtOH, whereby Compound I sodium Form I is formed.

In another embodiment, the disclosure provides a process for makingCompound I sodium Form II comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium with condition of <40% relative humidity, whereby Compound Isodium Form II is formed.

In another embodiment, the disclosure provides a process for makingCompound I sodium Form III comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium with IPA, whereby Compound I sodium Form III is formed.

In another embodiment, the disclosure provides a process for makingCompound I sodium Form IV comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium with IPAc, whereby Compound I sodium Form IV is formed.

In another embodiment, the disclosure provides a process for makingCompound I meglumine Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemeglumine with 1:1 toluene:heptane, whereby Compound I meglumine Form Iis formed.

In another embodiment, the disclosure provides a process for makingCompound I piperazine Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepiperazine with 1:1 ethanol:water, whereby Compound I piperazine Form Iis formed.

In another embodiment, the disclosure provides a process for makingCompound I choline Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidecholine with 1:1 toluene:heptane, whereby Compound I choline Form I isformed.

In another embodiment, the disclosure provides a process for makingCompound I deanol Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedeanol with diethyl ether, whereby Compound I deanol Form I is formed.

In another embodiment, the disclosure provides a process for makingCompound I 1-(2-hydroxyethyl)-pyrrolidine Form I comprising the step ofcontacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine with 18:83 ethyl acetate:methanol,whereby Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I is formed.

In another embodiment, the disclosure provides a process for makingCompound I 1-(2-hydroxyethyl)-pyrrolidine Form II comprising the step ofvacuum drying(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine, whereby Compound I1-(2-hydroxyethyl)-pyrrolidine Form II is formed.

In another embodiment, the disclosure provides a process for makingCompound I 1-(2-hydroxyethyl)-pyrrolidine Form III comprising the stepof contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyethyl)-pyrrolidine with 1:1 methyl-tert-butyl ether:toluene,whereby Compound I 1-(2-hydroxyethyl)-pyrrolidine Form III is formed.

In another embodiment, the disclosure provides a process for makingCompound I lysine Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidelysine with 80:20 ethanol:water, whereby Compound I lysine Form I isformed.

In another embodiment, the disclosure provides a process for makingCompound I arginine Form I comprising the step of contacting (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidearginine with 80:20 isopropyl alcohol:water, whereby Compound I arginineForm I is formed.

In another embodiment, the disclosure provides a process for makingCompound I potassium Form I comprising the step of contacting(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepotassium with isopropyl alcohol, whereby Compound I1-(2-hydroxyethyl)-potassium Form I is formed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of Compound I Form I.

FIG. 2 is differential scanning calorimetry (DSC) curve of Compound IForm I.

FIG. 3 is thermogravimetric analysis (TGA) of Compound I Form I.

FIG. 4 is dynamic vapor sorption (DVS) curve of Compound I Form I.

FIG. 5 is a nuclear magnetic resonance spectrum (¹H NMR) of Compound IForm I.

FIG. 6 is an X-ray powder diffraction pattern of Compound I Form II.

FIG. 7 is differential scanning calorimetry (DSC) curve of Compound IForm II.

FIG. 8 is thermogravimetric analysis (TGA) of Compound I Form II.

FIG. 9 is a nuclear magnetic resonance spectrum (¹H NMR) of Compound IForm II.

FIG. 10 is dynamic vapor sorption (DVS) curve of Compound I Form II.

FIG. 11 is single crystal analysis of Compound I Form II.

FIG. 12 is an X-ray powder diffraction pattern of Compound I Form III.

FIG. 13 is differential scanning calorimetry (DSC) curve of Compound IForm III.

FIG. 14 is thermogravimetric analysis (TGA) of Compound I Form III.

FIG. 15 is a nuclear magnetic resonance spectrum (¹H NMR) of Compound IForm III.

FIG. 16 is dynamic vapor sorption (DVS) curve of Compound I Form III.

FIG. 17 is an X-ray powder diffraction pattern of Compound I Form IV.

FIG. 18 is differential scanning calorimetry (DSC) curve of Compound IForm IV.

FIG. 19 is thermogravimetric analysis (TGA) of Compound I Form IV.

FIG. 20 is dynamic vapor sorption (DVS) curve of Compound I Form IV.

FIG. 21 is a nuclear magnetic resonance spectrum (¹H NMR) of Compound IForm IV.

FIG. 22 is an X-ray powder diffraction pattern of Compound I Form V.

FIG. 23 is differential scanning calorimetry (DSC) curve of Compound IForm V.

FIG. 24 is thermogravimetric analysis (TGA) of Compound I Form V.

FIG. 25 is dynamic vapor sorption (DVS) curve of Compound I Form V.

FIG. 26 is single crystal analysis of Compound I Form V.

FIG. 27 is an X-ray powder diffraction pattern of Compound I Form VI.

FIG. 28 is differential scanning calorimetry (DSC) curve of Compound IForm VI.

FIG. 29 is thermogravimetric analysis (TGA) of Compound I Form VI.

FIG. 30 is dynamic vapor sorption (DVS) curve of Compound I Form VI.

FIG. 31 is an X-ray powder diffraction pattern of Compound I Form VII.

FIG. 32 is differential scanning calorimetry (DSC) curve of Compound IForm VII.

FIG. 33 is a nuclear magnetic resonance spectrum (¹H NMR) of Compound IForm VII.

FIG. 34 is thermogravimetric analysis (TGA) of Compound I Form VII.

FIG. 35 is dynamic vapor sorption (DVS) curve of Compound I Form VII.

FIG. 36 is an X-ray powder diffraction pattern of Compound I Form VIII.

FIG. 37 is differential scanning calorimetry (DSC) curve of Compound IForm VIII.

FIG. 38 is thermogravimetric analysis (TGA) of Compound I Form VIII.

FIG. 39 is dynamic vapor sorption (DVS) curve of Compound I Form VIII.

FIG. 40 is an X-ray powder diffraction pattern of Compound I Form IX.

FIG. 41 is differential scanning calorimetry (DSC) curve of Compound IForm IX.

FIG. 42 is thermogravimetric analysis (TGA) of Compound I Form IX.

FIG. 43 is dynamic vapor sorption (DVS) curve of Compound I Form IX.

FIG. 44 is an X-ray powder diffraction pattern of Compound I Form X.

FIG. 45 is differential scanning calorimetry (DSC) curve of Compound IForm X.

FIG. 46 is thermogravimetric analysis (TGA) of Compound I Form X.

FIG. 47 is dynamic vapor sorption (DVS) curve of Compound I Form X.

FIG. 48 is an X-ray powder diffraction pattern of Compound I Form XI.

FIG. 49 is differential scanning calorimetry (DSC) curve of Compound IForm XI.

FIG. 50 is thermogravimetric analysis (TGA) of Compound I Form XI.

FIG. 51 is dynamic vapor sorption (DVS) curve of Compound I Form XI.

FIG. 52 is an X-ray powder diffraction pattern of Compound I Form XII.

FIG. 53 is differential scanning calorimetry (DSC) curve of Compound IForm XII.

FIG. 54 is thermogravimetric analysis (TGA) of Compound I Form XII.

FIG. 55 is dynamic vapor sorption (DVS) curve of Compound I Form XII.

FIG. 56 is an X-ray powder diffraction pattern of Compound I Form XIII.

FIG. 57 is differential scanning calorimetry (DSC) curve of Compound IForm XIII.

FIG. 58 is thermogravimetric analysis (TGA) of Compound I Form XIII.

FIG. 59 is dynamic vapor sorption (DVS) curve of Compound I Form XIII.

FIG. 60 is an X-ray powder diffraction pattern of Compound I Form XIV.

FIG. 61 is differential scanning calorimetry (DSC) curve of Compound IForm XIV.

FIG. 62 is thermogravimetric analysis (TGA) of Compound I Form XIV.

FIG. 63 is dynamic vapor sorption (DVS) curve of Compound I Form XIV.

FIG. 64 is an X-ray powder diffraction pattern of Compound I Form XV.

FIG. 65 is differential scanning calorimetry (DSC) curve of Compound IForm XV.

FIG. 66 is thermogravimetric analysis (TGA) of Compound I Form XV.

FIG. 67 is dynamic vapor sorption (DVS) curve of Compound I Form XV.

FIG. 68 is an X-ray powder diffraction pattern of Compound I Form XVI.

FIG. 69 is differential scanning calorimetry (DSC) curve of Compound IForm XVI.

FIG. 70 is thermogravimetric analysis (TGA) of Compound I Form XVI.

FIG. 71 is an X-ray powder diffraction pattern of Compound I Form XVII.

FIG. 72 is differential scanning calorimetry (DSC) curve of Compound IForm XVII.

FIG. 73 is thermogravimetric analysis (TGA) of Compound I Form XVII.

FIG. 74 is an X-ray powder diffraction pattern of Compound I Form XVIII.

FIG. 75 is differential scanning calorimetry (DSC) curve of Compound IForm XVIII.

FIG. 76 is thermogravimetric analysis (TGA) of Compound I Form XVIII.

FIG. 77 is dynamic vapor sorption (DVS) curve of Compound I Form XVIII.

FIG. 78 is an X-ray powder diffraction pattern of Compound I Form XIX.

FIG. 79 is differential scanning calorimetry (DSC) curve of Compound IForm XIX.

FIG. 80 is thermogravimetric analysis (TGA) of Compound I Form XIX.

FIG. 81 is an X-ray powder diffraction pattern of Compound I Form XX.

FIG. 82 is differential scanning calorimetry (DSC) curve of Compound IForm XX.

FIG. 83 is thermogravimetric analysis (TGA) of Compound I Form XX.

FIG. 84 is dynamic vapor sorption (DVS) curve of Compound I Form XX.

FIG. 85 is an X-ray powder diffraction pattern of Compound I Form XXI.

FIG. 86 is differential scanning calorimetry (DSC) curve of Compound IForm XXI.

FIG. 87 is thermogravimetric analysis (TGA) of Compound I Form XXI.

FIG. 88 is dynamic vapor sorption (DVS) curve of Compound I Form XXI.

FIG. 89 is an X-ray powder diffraction pattern of Compound I sodium FormI.

FIG. 90 is differential scanning calorimetry (DSC) curve of Compound Isodium Form I.

FIG. 91 is thermogravimetric analysis (TGA) of Compound I sodium Form I.

FIG. 92 is dynamic vapor sorption (DVS) curve of Compound I sodium FormI.

FIG. 93 is an X-ray powder diffraction pattern of Compound I sodium FormII.

FIG. 94 is differential scanning calorimetry (DSC) curve of Compound Isodium Form II.

FIG. 95 is thermogravimetric analysis (TGA) of Compound I sodium FormII.

FIG. 96 is dynamic vapor sorption (DVS) curve of Compound I sodium FormII.

FIG. 97 is an X-ray powder diffraction pattern of Compound I sodium FormIII.

FIG. 98 is differential scanning calorimetry (DSC) curve of Compound Isodium Form III.

FIG. 99 is thermogravimetric analysis (TGA) of Compound I sodium FormIII.

FIG. 100 is dynamic vapor sorption (DVS) curve of Compound I sodium FormIII.

FIG. 101 is an X-ray powder diffraction pattern of Compound I sodiumForm IV.

FIG. 102 is differential scanning calorimetry (DSC) curve of Compound Isodium Form IV.

FIG. 103 is thermogravimetric analysis (TGA) of Compound I sodium FormIV.

FIG. 104 is dynamic vapor sorption (DVS) curve of Compound I sodium FormIV.

FIG. 105 is an X-ray powder diffraction pattern of Compound I meglumineForm I.

FIG. 106 is differential scanning calorimetry (DSC) curve of Compound Imeglumine Form I.

FIG. 107 is thermogravimetric analysis (TGA) of Compound I meglumineForm I.

FIG. 108 is an X-ray powder diffraction pattern of Compound I piperazineForm I.

FIG. 109 is differential scanning calorimetry (DSC) curve of Compound Ipiperazine Form I.

FIG. 110 is thermogravimetric analysis (TGA) of Compound I piperazineForm I.

FIG. 111 is an X-ray powder diffraction pattern of Compound I cholineForm I.

FIG. 112 is differential scanning calorimetry (DSC) curve of Compound Icholine Form I.

FIG. 113 is thermogravimetric analysis (TGA) of Compound I choline FormI.

FIG. 114 is an X-ray powder diffraction pattern of Compound I deanolForm I.

FIG. 115 is an X-ray powder diffraction pattern of Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form I.

FIG. 116 is differential scanning calorimetry (DSC) curve of Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form I.

FIG. 117 is thermogravimetric analysis (TGA) of Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form I.

FIG. 118 is an X-ray powder diffraction pattern of Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form II.

FIG. 119 is an X-ray powder diffraction pattern of Compound I1-(2-hydroxyethyl)-pyrrolidine (HEP) Form III.

FIG. 120 is an X-ray powder diffraction pattern of Compound I lysineForm I.

FIG. 121 is an X-ray powder diffraction pattern of Compound I arginineForm I.

FIG. 122 is an X-ray powder diffraction pattern of Compound I potassiumForm I.

FIG. 123 is differential scanning calorimetry (DSC) curve of Compound Ipotassium Form I.

FIG. 124 is thermogravimetric analysis (TGA) of Compound I potassiumForm I.

FIG. 125 is dynamic vapor sorption (DVS) curve of Compound I potassiumForm I.

DETAILED DESCRIPTION

Compound named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide,is a selective and potent inhibitor of HCV NS3 and has the structure asfollows:

The present disclosure relates to various crystalline forms of CompoundI, and processes for making the crystalline forms. Compound I alsoprovides forms further described herein as “Compound I Form I,”“Compound I Form II,” “Compound I Form III,” “Compound I Form IV,”“Compound I Form V,” “Compound I Form VI,” “Compound I Form VII,”“Compound I Form VIII,” “Compound I Form IX,” “Compound I Form X,”“Compound I Form XI,” “Compound I Form XII,” “Compound I Form XIII,”“Compound I Form XIV,” “Compound I Form XV,” “Compound I Form XVI,”“Compound I Form XVII,” “Compound I Form XVIII,” “Compound I Form XIX,”“Compound I Form XX,” “Compound I Form XXI,” In some embodiments, suchforms of Compound I may be a solvate.

Additional crystalline forms of Compound I are also further describedherein. In some embodiments, crystalline forms of Compound I may includesalts or co-crystals of Compound I. Salts or co-crystals of Compound Imay have the following formula:

In some embodiments, Y may be sodium, meglumine, piperazine, choline,deanol, 1-(2-hydroxyethyl)-pyrrolidine, lysine or arginine. Thefollowing exemplary forms are further described herein: “Compound Isodium Form I,” “Compound I sodium Form II,” “Compound I sodium FormIII,” “Compound I sodium Form IV,” “Compound I meglumine Form I,”“Compound I piperazine Form I,” “Compound I choline Form I,” “Compound Ideanol Form I,” “Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I,”“Compound I 1-(2-hydroxyethyl)-pyrrolidine Form II,” “Compound I1-(2-hydroxyethyl)-pyrrolidine Form III,” “Compound I lysine Form I,”“Compound I arginine Form I,” and “Compound I potassium Form I.”

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “solvate” refers to a complex formed by the combining ofCompound I and a solvent.

The term “desolvated” refers to a Compound I form that is a solvate asdescribed herein, and from which solvent molecules have been partiallyor completely removed. Desolvation techniques to produce desolvatedforms include, without limitation, exposure of a Compound I form(solvate) to a vacuum, subjecting the solvate to elevated temperature,exposing the solvate to a stream of gas, such as air or nitrogen, or anycombination thereof. Thus, a desolvated Compound I form can beanhydrous, i.e., completely without solvent molecules, or partiallysolvated wherein solvent molecules are present in stoichiometric ornon-stoichiometric amounts.

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject being treated, the weight and ageof the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

The term “about” refers to a range of ±10%, unless otherwise specified.

The term “co-crystal” refers to a crystalline material formed bycombining a compound of Formula I, or any Formula disclosed herein andone or more co-crystal formers (i.e., a molecule, ion or atom). Incertain instances, co-crystals may have improved properties as comparedto the parent form (i.e., the free molecule, zwitterion, etc.) or a saltof the parent compound. Improved properties can be increased solubility,increased dissolution, increased bioavailability, increased doseresponse, decreased hygroscopicity, a crystalline form of a normallyamorphous compound, a crystalline form of a difficult to salt orunsaltable compound, decreased form diversity, more desired morphology,and the like. Methods for making and characterizing co-crystals areknown to those of skill in the art.

Salts of the compounds disclosed herein can be base addition salts oracid addition salts depending on the reactivity of the functional groupspresent on the specific compound. Base addition salts can be derivedfrom inorganic or organic bases. Salts derived from inorganic basesinclude, by way of example only, sodium, potassium, lithium, ammonium,calcium and magnesium salts. Salts derived from organic bases include,but are not limited to, salts of primary, secondary and tertiary amines,such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkylamines, di(substituted alkyl) amines, tri(substituted alkyl) amines,alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenylamines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. Amines are of general structure N(R³⁰)(R³¹)(R³²),wherein mono-substituted amines have 2 of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines have 1 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen,whereas tri-substituted amines have none of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ and R³² are selectedfrom a variety of substituents such as hydrogen, optionally substitutedalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl and thelike. The above-mentioned amines refer to the compounds wherein eitherone, two or three substituents on the nitrogen are as listed in thename. For example, the term “cycloalkenyl amine” refers tocycloalkenyl-NH₂, wherein “cycloalkenyl” is as defined herein. The term“diheteroarylamine” refers to NH(heteroaryl)₂, wherein “heteroaryl” isas defined herein and so on.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Acid addition salts can be derived from inorganic or organic acids.Salts derived from inorganic acids include hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Salts derived from organic acids include acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and thelike.

Any of the salts disclosed herein may be optionally pharmaceuticallyacceptable. The term “pharmaceutically acceptable salt” of a givencompound refers to salts that retain the biological effectiveness andproperties of the given compound, and which are not biologically orotherwise undesirable. See: P. Heinrich Stahl and Camille G. Wermuth(Eds.) Pharmaceutical Salts: Properties, Selection, and Use(International Union of Pure and Applied Chemistry), Wiley-VCH; 2ndRevised Edition (May 16, 2011). Pharmaceutically acceptable baseaddition salts can be prepared from inorganic and organic bases.

Pharmaceutically acceptable base addition salts may be salts preparedfrom inorganic and organic bases and pharmaceutically acceptable acidaddition salts may be salts prepared from inorganic and organic acids.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. In someembodiments, the alkyl has 1 to 15 carbon atoms, or from 1 to 10 carbonatoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms, or from1 to 4 carbon atoms. This term is exemplified by groups such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl,n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl,        —S(O)— cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,        —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,        —S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2 or 3 substituents        chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and        —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and        n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

As used herein, the term “interrupted by” means a carbon atom of a group(e.g. an alkyl group) is replaced by a heteroatom.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3, 4, 5 or 6 carbon atoms.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl. This term is exemplified by groupssuch as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,t-butoxy, n-hexyloxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is substituted alkylene and Z issubstituted alkenyl or substituted alkynyl, where substituted alkyl,substituted alkenyl and substituted alkynyl are as defined herein.

The term “C₁₋₃ haloalkyl” refers to an alkyl group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In someembodiments, C₁₋₃ haloalkyl includes, by way of example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, 3,3,3-trifluoropropyl,3,3-difluoropropyl, 3-fluoropropyl.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. The term “substituted cycloalkyl”also includes cycloalkyl groups wherein one or more of the annularcarbon atoms of the cycloalkyl group has an oxo group bonded thereto. Inaddition, a substituent on the cycloalkyl or cycloalkenyl may beattached to the same carbon atom as, or is geminal to, the attachment ofthe substituted cycloalkyl or cycloalkenyl to the 6,7-ring system.Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1, 2 or 3 substituents chosen fromalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms(in some embodiments from 1 to 4 heteroatoms), selected from nitrogen,sulfur, phosphorus, and/or oxygen within the ring. In some embodiments,the “heterocyclyl,” “heterocycle,” or “heterocyclic” group is linked tothe remainder of the molecule through one of the heteroatoms within thering.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. In addition, a substituent on theheterocyclic group may be attached to the same carbon atom as, or isgeminal to, the attachment of the substituted heterocyclic group to the6,7-ring system. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examplesof heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridylor furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazoleor benzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

All or most of the XRPD patterns of various forms of Compound I werecollected with a PANalytical X'Pert PRO MPD diffractometer using thefollowing experimental setting: 45 kV, 40 mA, Kα1=1.5406 Å, scan range2-40 °2θ, step size 0.0167 °2θ, counting time: 15.875 s or 48.260 s. TheDSC analysis was conducted on a TA Instruments Q2000 differentialscanning calorimeter using approximately 2-3 mg of material, 10° C./minheating rate over a typical range of (−30° C.)-300° C. or 20° C.-350° C.The TGA data were obtained on a TA Instruments 2950 and Q5000thermogravimetric analyzers using approximately 2-5 mg of material, 10°C./min heating rate over a typical range of 25-350° C.

In addition, abbreviations as used herein have respective meanings asfollows:

δ Chemical shift 2-Me - THF or MeTHF 2-methyltetrahydrofuran amu Atomicmass unit atm Standard atmosphere Ac acetate Boc tert-butoxycarbonyl brbroad CPME Cyclopentyl methyl ether Cy cylcohexyl d doublet dd doubletof doublets ddd doublet of doublet of doublets DCM dichloromethane DMAor DMAc N,N-dimethylacetamide DMF dimethylformamide dq doublet ofquartets dt doublet of triplets DSC differential scanning calorimetryDVS Dynamic vapor sorption EDC•HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EDTA Ethylenediaminetetraacetic acidequiv or eq. equivalents Et ethyl EtOAc ethyl acetate EtOH ethanol ggram h/hrs hour(s) HEP 1-(2-hydroxyethyl)-pyrrolidine HOBt1-hydroxybenzotriazole hydrate Hz hertz IPA isopropanol IPAc isopropylacetate iPr isopropyl J Coupling constant L liter LC Liquidchromatography LCMS Liquid chromatography mass spectrometry M molar mmultiplet m/z Mass to charge Me methyl MEK methyl ethyl ketone MeOHmethanol mg milligram MIBK methyl isobutyl ketone MHz megahertz mLmilliliter mmol millimole mol mole MS mass spectroscopy MTBE Methyltert-butyl ether N Normal NMM N-methylmorpholine NMR nuclear magneticresonance Ph phenyl ppm parts per million psig pounds per square inch qquartet R.H. or RH Relative humidity s singlet t triplet td Triplet ofdoublets tdd Triplet of doublet of doublets tBu tert-butyl TGAthermogravimetric analysis Ts tosyl THF tetrahydrofuran UPLC ultraperformance liquid chromatography μL microliter μg microgram vol volumev/v volume to volume w/w or wt/wt weight to weight wt. weight XRPD X-raypowder diffraction

Crystalline Forms of Compound I

As described generally above, the present disclosure providescrystalline forms of Compound I and Compound I salts/co-crystals, whichare disclosed herein.

Compound I Form I is characterized by an X-ray powder diffractogramcomprising peaks at 8.6, 11.1, and 15.5 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 12.9 °2θ±0.2 °2θ. Form I is also characterized by itsfull X-ray powder diffractogram as substantially shown in FIG. 1.

In some embodiments, Form I is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 2.

In some embodiments, Form I is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG. 3.

In some embodiments, Form I is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 4.

In some embodiments, Form I is also characterized by a nuclear magneticresonance spectrum (¹H NMR) substantially as shown in FIG. 5.

In one embodiment, Form I comprises about 1.7 mole equivalents ofethanol.

Compound I Form II is characterized by an X-ray powder diffractogramcomprising peaks at 8.7, 13.0, and 17.4 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 15.4 °2θ±0.2 °2θ. Form II is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 6.

In some embodiments, Form II is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 7.

In some embodiments, Form II is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG. 8.

In some embodiments, Form II is also characterized by a nuclear magneticresonance spectrum (¹H NMR) substantially as shown in FIG. 9.

In some embodiments, Form II is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 10.

In one embodiment, Form II comprises about 1 mole equivalent of ethylacetate.

Compound I Form III is characterized by an X-ray powder diffractogramcomprising peaks at 11.1, 12.8, and 19.7 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 15.5 °2θ±0.2 °2θ. Form III is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 12.

In some embodiments, Form III is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 13.

In some embodiments, Form III is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.14.

In some embodiments, Form III is also characterized by a nuclearmagnetic resonance spectrum (¹H NMR) substantially as shown in FIG. 15.In some embodiments, Form III is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 16.

In one embodiment, Form III comprises about 1.4 mole equivalents ofisopropanol.

Compound I Form IV is characterized by an X-ray powder diffractogramcomprising peaks at 8.7, 8.9, and 16.0 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 13.0 °2θ±0.2 °2θ. Form IV is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 17.

In some embodiments, Form IV is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 18.

In some embodiments, Form IV is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.19.

In some embodiments, Form IV is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 20.

In one embodiment, Form IV comprises about 2.2 mole equivalents ofwater.

In some embodiments, Form IV is also characterized by a nuclear magneticresonance spectrum (¹H NMR) substantially as shown in FIG. 21.

Compound I Form V is characterized by an X-ray powder diffractogramcomprising peaks at 6.2, 12.4, and 19.6 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 13.7 °2θ±0.2 °2θ. Form V is also characterized by itsfull X-ray powder diffractogram as substantially shown in FIG. 22.

In some embodiments, Form V is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 23.

In some embodiments, Form V is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.24.

In some embodiments, Form V is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 25.

In one embodiment, Form V comprises from about >1 to about 2.5 moleequivalents of methanol. In another embodiment, Form V comprises about2.5 mole equivalents of methanol.

Compound I Form VI is characterized by an X-ray powder diffractogramcomprising peaks at 14.6, 15.4, and 20.0 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 18.1 °2θ±0.2 °2θ. Form VI is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 27.

In some embodiments, Form VI is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 28.

In some embodiments, Form VI is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.29.

In some embodiments, Form VI is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 30.

Compound I Form VII is characterized by an X-ray powder diffractogramcomprising peaks at 6.5, 8.5, and 18.7 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 17.5 °2θ±0.2 °2θ. Form VII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 31.

In some embodiments, Form VII is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 32.

In some embodiments, Form VII is also characterized by a nuclearmagnetic resonance spectrum (¹H NMR) substantially as shown in FIG. 33.In some embodiments, Form VII is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.34.

In some embodiments, Form VII is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 35.

Compound I Form VIII is characterized by an X-ray powder diffractogramcomprising peaks at 7.8, 8.2, and 20.2 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 16.5 °2θ±0.2 °2θ. Form VIII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 36.

In some embodiments, Form VIII is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 37.

In some embodiments, Form VIII is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 38.

In some embodiments, Form VIII is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 39.

Compound I Form IX is characterized by an X-ray powder diffractogramcomprising peaks at 6.1, 9.5, and 19.4 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 20.8 °2θ±0.2 °2θ. Form IX is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 40.

In some embodiments, Form IX is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 41.

In some embodiments, Form IX is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.42.

In some embodiments, Form IX is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 43.

Compound I Form X is characterized by an X-ray powder diffractogramcomprising peaks at 8.0, 19.0, and 20.4 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 13.9 °2θ±0.2 °2θ. Form X is also characterized by itsfull X-ray powder diffractogram as substantially shown in FIG. 44.

In some embodiments, Form X is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 45.

In some embodiments, Form X is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.46.

In some embodiments, Form X is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 47.

In one embodiment, Form X comprises about 0.58 mole equivalents ofwater.

Compound I Form XI is characterized by an X-ray powder diffractogramcomprising peaks at 11.0, 13.9, and 20.9 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 15.2 °2θ±0.2 °2θ. Form XI is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 48.

In some embodiments, Form XI is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 49.

In some embodiments, Form XI is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.50.

In some embodiments, Form XI is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 51.

In one embodiment, Form XI comprises about 2.3 mole equivalents ofwater.

Compound I Form XII is characterized by an X-ray powder diffractogramcomprising peaks at 12.4, 14.6, and 19.3 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 15.4 °2θ±0.2 °2θ. Form XII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 52.

In some embodiments, Form XII is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 53.

In some embodiments, Form XII is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.54.

In some embodiments, Form XII is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 55.

In one embodiment, Form XII comprises about 3.7 mole equivalents ofwater.

Compound I Form XIII is characterized by an X-ray powder diffractogramcomprising peaks at 8.5, 11.0, and 15.4 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 22.2 °2θ±0.2 °2θ. Form XIII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 56.

In some embodiments, Form XIII is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 57.

In some embodiments, Form XIII is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 58.

In some embodiments, Form XIII is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 59.

Compound I Form XIV is characterized by an X-ray powder diffractogramcomprising peaks at 11.2, 15.7, and 17.9 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 23.1 °2θ±0.2 °2θ. Form XIV is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 60.

In some embodiments, Form XIV is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 61.

In some embodiments, Form XIV is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.62.

In some embodiments, Form XIV is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 63.

Compound I Form XV is characterized by an X-ray powder diffractogramcomprising peaks at 9.7, 11.0, and 15.5 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 19.7 °2θ±0.2 °2θ. Form XV is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 64.

In some embodiments, Form XV is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 65.

In some embodiments, Form XV is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.66.

In some embodiments, Form XV is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 67.

Compound I Form XVI is characterized by an X-ray powder diffractogramcomprising peaks at 5.8, 7.8, and 18.8 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 25.0 °2θ±0.2 °2θ. Form XVI is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 68.

In some embodiments, Form XVI is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 69.

In some embodiments, Form XVI is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.70.

Compound I Form XVII is characterized by an X-ray powder diffractogramcomprising peaks at 7.9, 18.9, and 20.3 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 21.5 °2θ±0.2 °2θ. Form XVII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 71.

In some embodiments, Form XVII is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 72.

In some embodiments, Form XVII is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 73.

Compound I Form XVIII is characterized by an X-ray powder diffractogramcomprising peaks at 5.6, 6.4, and 7.5 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 16.6 °2θ±0.2 °2θ. Form XVIII is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 74.

In some embodiments, Form XVIII is also characterized by itsdifferential scanning calorimetry (DSC) curve substantially as shown inFIG. 75.

In some embodiments, Form XVIII is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 76.

In some embodiments, Form XVIII is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 77.

Compound I Form XIX is characterized by an X-ray powder diffractogramcomprising peaks at 11.1, 15.5, and 19.8 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 23.3 °2θ±0.2 °2θ. Form XIX is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 78.

In some embodiments, Form XIX is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 79.

In some embodiments, Form XIX is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.80.

Compound I Form XX is characterized by an X-ray powder diffractogramcomprising peaks at 11.9, 14.5, and 19.1 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 30.0 °2θ±0.2 °2θ. Form XX is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 81.

In some embodiments, Form XX is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 82.

In some embodiments, Form XX is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.83.

In some embodiments, Form XX is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 84.

Compound I Form XXI is characterized by an X-ray powder diffractogramcomprising peaks at 11.9, 12.2, and 14.4 °2θ±0.2 °2θ, as determined on adiffractometer using Cu—Kα radiation. The diffractogram comprises anadditional peak at 19.1 °2θ±0.2 °2θ. Form XXI is also characterized byits full X-ray powder diffractogram as substantially shown in FIG. 85.

In some embodiments, Form XXI is also characterized by its differentialscanning calorimetry (DSC) curve substantially as shown in FIG. 86.

In some embodiments, Form XXI is also characterized by thermogravimetricanalysis (TGA) comprising a thermogram substantially as shown in FIG.87.

In some embodiments, Form XXI is also characterized by a dynamic vaporsorption (DVS) curve substantially as shown in FIG. 88.

Compound I sodium Form I is characterized by an X-ray powderdiffractogram comprising peaks at 5.6, 7.8, and 11.2 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 18.4 °2θ±0.2 °2θ. Compound I sodium FormI is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 89.

In some embodiments, Compound I sodium Form I is also characterized byits differential scanning calorimetry (DSC) curve substantially as shownin FIG. 90.

In some embodiments, Compound I sodium Form I is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 91.

In some embodiments, Compound I sodium Form I is also characterized by adynamic vapor sorption (DVS) curve substantially as shown in FIG. 92.

Compound I sodium Form II is characterized by an X-ray powderdiffractogram comprising peaks at 5.8, 7.3, and 11.1 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 19.0 °2θ±0.2 °2θ. Compound I sodium FormII is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 93.

In some embodiments, Compound I sodium Form II is also characterized byits differential scanning calorimetry (DSC) curve substantially as shownin FIG. 94.

In some embodiments, Compound I sodium Form II is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 95.

In some embodiments, Compound I sodium Form II is also characterized bya dynamic vapor sorption (DVS) curve substantially as shown in FIG. 96.

Compound I sodium Form III is characterized by an X-ray powderdiffractogram comprising peaks at 5.4, 7.7, and 10.8 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 17.7 °2θ±0.2 °2θ. Compound I sodium FormIII is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 97.

In some embodiments, Compound I sodium Form III is also characterized byits differential scanning calorimetry (DSC) curve substantially as shownin FIG. 98.

In some embodiments, Compound I sodium Form III is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 99.

In some embodiments, Compound I sodium Form III is also characterized bya dynamic vapor sorption (DVS) curve substantially as shown in FIG. 100.

Compound I sodium Form IV is characterized by an X-ray powderdiffractogram comprising peaks at 10.4, 12.1, and 16.6 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 19.4 °2θ±0.2 °2θ. Compound I sodium FormIV is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 101.

In some embodiments, Compound I sodium Form IV is also characterized byits differential scanning calorimetry (DSC) curve substantially as shownin FIG. 102.

In some embodiments, Compound I sodium Form IV is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 103.

In some embodiments, Compound I sodium Form IV is also characterized bya dynamic vapor sorption (DVS) curve substantially as shown in FIG. 104.

Compound I meglumine Form I is characterized by an X-ray powderdiffractogram comprising peaks at 3.6, 5.1, and 8.9 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 18.2 °2θ±0.2 °2θ. Compound I meglumineForm I is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 105.

In some embodiments, Compound I meglumine Form I is also characterizedby its differential scanning calorimetry (DSC) curve substantially asshown in FIG. 106.

In some embodiments, Compound I meglumine Form I is also characterizedby thermogravimetric analysis (TGA) comprising a thermogramsubstantially as shown in FIG. 107.

Compound I piperazine Form I is characterized by an X-ray powderdiffractogram comprising peaks at 4.9, 7.2, and 8.2 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 10.9 °2θ±0.2 °2θ. Compound I piperazineForm I is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 108.

In some embodiments, Compound I piperazine Form I is also characterizedby its differential scanning calorimetry (DSC) curve substantially asshown in FIG. 109.

In some embodiments, Compound I piperazine Form I is also characterizedby thermogravimetric analysis (TGA) comprising a thermogramsubstantially as shown in FIG. 110.

Compound I choline Form I is characterized by an X-ray powderdiffractogram comprising peaks at 7.4, 15.5, and 20.9 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 23.5 °2θ±0.2 °2θ. Compound I cholineForm I is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 111.

In some embodiments, Compound I choline Form I is also characterized byits differential scanning calorimetry (DSC) curve substantially as shownin FIG. 112.

In some embodiments, Compound I choline Form I is also characterized bythermogravimetric analysis (TGA) comprising a thermogram substantiallyas shown in FIG. 113.

Compound I deanol Form I is characterized by an X-ray powderdiffractogram comprising peaks at 7.4, 10.7, and 15.2 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 20.8 °2θ±0.2 °2θ. Compound I deanol FormI is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 114.

Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I is characterized by anX-ray powder diffractogram comprising peaks at 8.2, 10.8, and 19.9°2θ±0.2 °2θ, as determined on a diffractometer using Cu—Kα radiation.The diffractogram comprises an additional peak at 21.1 ° 2θ±0.2 °2θ.Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I is also characterizedby its full X-ray powder diffractogram as substantially shown in FIG.115.

In some embodiments, Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I isalso characterized by its differential scanning calorimetry (DSC) curvesubstantially as shown in FIG. 116.

In some embodiments, Compound I 1-(2-hydroxyethyl)-pyrrolidine Form I isalso characterized by thermogravimetric analysis (TGA) comprising athermogram substantially as shown in FIG. 117.

Compound I 1-(2-hydroxyethyl)-pyrrolidine Form II is characterized by anX-ray powder diffractogram comprising peaks at 7.7, 8.3, and 15.5°2θ±0.2 °2θ, as determined on a diffractometer using Cu—Kα radiation.The diffractogram comprises an additional peak at 20.9 °2θ±0.2 °2θ.Compound I 1-(2-hydroxyethyl)-pyrrolidine Form II is also characterizedby its full X-ray powder diffractogram as substantially shown in FIG.118.

Compound I 1-(2-hydroxyethyl)-pyrrolidine Form III is characterized byan X-ray powder diffractogram comprising peaks at 7.1, 8.0, and 10.7°2θ±0.2 °2θ, as determined on a diffractometer using Cu—Kα radiation.The diffractogram comprises an additional peak at 21.4 °2θ±0.2 °2θ.Compound I 1-(2-hydroxyethyl)-pyrrolidine Form III is also characterizedby its full X-ray powder diffractogram as substantially shown in FIG.119.

Compound I lysine Form I is characterized by an X-ray powderdiffractogram comprising peaks at 4.2, 8.3, and 9.5 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 22.0 °2θ±0.2 °2θ. Compound I lysine FormI is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 120.

Compound I arginine Form I is characterized by an X-ray powderdiffractogram comprising peaks at 7.1, 8.1, and 9.5 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 10.8 °2θ±0.2 °2θ. Compound I arginineForm I is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 121.

Compound I potassium Form I is characterized by an X-ray powderdiffractogram comprising peaks at 6.4, 8.6, and 15.8 °2θ±0.2 °2θ, asdetermined on a diffractometer using Cu—Kα radiation. The diffractogramcomprises an additional peak at 20.4 °2θ±0.2 °2θ. Compound I potassiumForm I is also characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 122.

In some embodiments, Compound I potassium Form I is also characterizedby its differential scanning calorimetry (DSC) curve substantially asshown in FIG. 123.

In some embodiments, Compound I potassium Form I is also characterizedby thermogravimetric analysis (TGA) comprising a thermogramsubstantially as shown in FIG. 124.

In some embodiments, Compound I potassium Form I is also characterizedby a dynamic vapor sorption (DVS) curve substantially as shown in FIG.125.

Pharmaceutical Formulations

The Compound I forms of this disclosure are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as, for example, those set forth in the Handbook of PharmaceuticalExcipients (1986). Excipients include ascorbic acid and otherantioxidants, chelating agents such as, for example, EDTA, carbohydratessuch as, for example, dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. The pH of theformulations ranges from about 3 to about 11, but is ordinarily about 7to 10. It is contemplated that the Compound I form may be administeredonce, twice or three times a day.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the disclosurecomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefore and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present disclosure suitable for oral administrationmay be presented as discrete units such as, for example, capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas, for example, a powder or granules, optionally mixed with a binder,lubricant, inert diluent, or preservative. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as, for example, 0.6% w/w, 0.7%w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10%w/w. When formulated in an ointment, the active ingredients may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as, for example, propyleneglycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethyleneglycol (including PEG 400) and mixtures thereof. The topicalformulations may desirably include a Compound I form which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulphoxide and related analogs.

The oily phase of the emulsions of this disclosure may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the disclosure include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as, for example,di-isoadipate, isocetyl stearate, propylene glycol diester of coconutfatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate,butyl stearate, 2-ethylhexyl palmitate or a blend of branched chainesters known as Crodamol CAP may be used, the last three being preferredesters. These may be used alone or in combination depending on theproperties required. Alternatively, high melting point lipids such as,for example, white soft paraffin and/or liquid paraffin or other mineraloils are used.

Pharmaceutical formulations according to the present disclosure compriseone or more Compound I forms of the disclosure together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, emulsions, hard or soft capsules,syrups or elixirs may be prepared. Compositions intended for oral usemay be prepared according to any method known to the art for themanufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as, for example, calcium or sodiumcarbonate, lactose, lactose monohydrate, croscarmellose sodium,povidone, calcium or sodium phosphate; granulating and disintegratingagents, such as, for example, maize starch, or alginic acid; bindingagents, such as, for example, cellulose, microcrystalline cellulose,starch, gelatin or acacia; and lubricating agents, such as, for example,magnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as, for example, glyceryl monostearate or glyceryldistearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such as, forexample, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the disclosure contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as, forexample, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanthand gum acacia, and dispersing or wetting agents such as, for example, anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethyleneoxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such as,for example, ethyl or n-propyl p-hydroxy-benzoate, one or more coloringagents, one or more flavoring agents and one or more sweetening agents,such as, for example, sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as, for example, liquidparaffin. The oral suspensions may contain a thickening agent, such as,for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents,such as, for example, those set forth above, and flavoring agents may beadded to provide a palatable oral preparation. These compositions may bepreserved by the addition of an antioxidant such as, for example,ascorbic acid.

Granules of the disclosure suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, a suspending agent, andone or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those disclosed above. Additionalexcipients, for example sweetening, flavoring and coloring agents, mayalso be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,such as, for example, olive oil or arachis oil, a mineral oil, such as,for example, liquid paraffin, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as, forexample, gum acacia and gum tragacanth, naturally occurringphosphatides, such as, for example, soybean lecithin, esters or partialesters derived from fatty acids and hexitol anhydrides, such as, forexample, sorbitan monooleate, and condensation products of these partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. The emulsion may also contain sweetening andflavoring agents. Syrups and elixirs may be formulated with sweeteningagents, such as, for example, glycerol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringor a coloring agent.

The pharmaceutical compositions of the disclosure may be in the form ofa sterile injectable preparation, such as, for example, a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as, for example, a solution in 1,3-butane-diol or preparedas a lyophilized powder. Among the acceptable vehicles and solvents thatmay be employed are water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile fixed oils may conventionally beemployed as a solvent or suspending medium. For this purpose any blandfixed oil may be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as, for example, oleic acid may likewise beused in the preparation of injectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Insome embodiments, the pharmaceutical compositions described hereincontain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1-300 mg, 1 to 200mg, 1 to 100 mg or 1 to 50 mg of a Compound I Form (such as FormsI-XXI). In some embodiments, the pharmaceutical compositions describedherein contain not more than about 400 mg, preferably not more thanabout 300 mg, of Compound I Form (such as Forms I-XXI). In someembodiments, the pharmaceutical compositions described herein containabout 10, 25, or 50 mg of Compound I Form (such as Forms I-XXI). Inother embodiments, the pharmaceutical compositions described hereincontain about 100 mg of a Compound I Form (such as Forms I-XXI).

The pharmaceutical composition can be prepared to provide easilymeasurable amounts for administration. For example, an aqueous solutionintended for intravenous infusion may contain from about 3 to 500 μg ofthe active ingredient per milliliter of solution in order that infusionof a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10%, particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as, for example, gelatin and glycerin,or sucrose and acacia; and mouthwashes comprising the active ingredientin a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as, for example, 0.5, 1, 30 microns, 35 microns, etc.),which is administered by rapid inhalation through the nasal passage orby inhalation through the mouth so as to reach the alveolar sacs.Suitable formulations include aqueous or oily solutions of the activeingredient. Formulations suitable for aerosol or dry powderadministration may be prepared according to conventional methods and maybe delivered with other therapeutic agents such as, for example,compounds heretofore used in the treatment or prophylaxis of conditionsassociated with HCV activity.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this disclosure may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The disclosure further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compound I forms of the disclosure can also be formulated to providecontrolled release of the active ingredient to allow less frequentdosing or to improve the pharmacokinetic or toxicity profile of theactive ingredient. Accordingly, the disclosure also providescompositions comprising one or more Compound I forms of the disclosureformulated for sustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

In one embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a compound selected from the group consisting ofCompound I Form I, Compound I Form II, Compound I Form III, Compound IForm IV, Compound I Form V, Compound I Form VI, Compound I Form VII,Compound I Form VIII, Compound I Form IX, Compound I Form X, Compound IForm XI, Compound I Form XII, Compound I Form XIII, Compound I Form XIV,Compound I Form XV, Compound I Form XVI, Compound I Form XVII, CompoundI Form XVIII, Compound I Form XIX, Compound I Form XX, and Compound IForm XXI and a pharmaceutically acceptable excipient.

Methods of Use

The crystalline forms of Compound I described herein are administered toa subject suffering from hepatitis C virus (HCV) in either single ormultiple doses by any of the accepted modes of administration known tothose who are skilled in the art. Administration routes include, forexample, those described in any patents and patent applicationsincorporated by reference, such as rectal, buccal, intranasal andtransdermal routes, by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, as an inhalant, or via an impregnated or coateddevice such as a stent, for example, or an artery-inserted cylindricalpolymer.

Oral administration can be carried out by delivering any of the CompoundI forms by capsule or enteric coated tablets, or the like.

The Compound I forms also can be administered by transdermal deliverydevices (“patches”). Such transdermal patches may be used to providecontinuous or discontinuous infusion of the compounds of the presentdisclosure in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

The compounds are preferably formulated in a unit dosage form. The term“unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect. The compounds are generallyadministered in a pharmaceutically effective amount.

For oral administration, each dosage unit typically contains from 1 mgto 2 g of a compound described herein. It will be understood, however,that the amount of the compound actually administered usually will bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered and its relativeactivity, the age, weight, and response of the individual patient, theseverity of the patient's symptoms, and the like.

Combination Therapy

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a Compound I Form (such as FormsI-XXI), in combination with at least one additional therapeutic agent(i.e., active ingredient), and a pharmaceutically acceptable carrier orexcipient. In certain embodiments, additional therapeutic agents includeadditional antiviral agents.

The additional therapeutic agent used in combination with the compoundsdescribed herein includes, without limitation, any agent having atherapeutic effect when used in combination with the compound of thepresent invention. Such combinations are selected based on the conditionto be treated, cross-reactivities of ingredients and pharmaco-propertiesof the combination. For example, in certain embodiments, the therapeuticagent used in combination with the Compound I Form (such as Forms I-XXI)include, without limitation, one of more of the following: interferons,ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, NS5binhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,non-nucleoside inhibitors of HCV, nucleoside analogues, and other drugsfor treating HCV infection. In some embodiments, the additionaltherapeutic agents include, without limitation, NS3 protease inhibitors,NS5a inhibitors, and/or NS5b inhibitors. In some embodiments, apharmaceutical composition including a compound I Form and one or moreof an NS3 protease inhibitor, an NS5a inhibitor, and/or an NS5binhibitor is provided. In some embodiments, a pharmaceutical compositionincluding a Compound I Form (such as Forms I-XXI), or a pharmaceuticallyacceptable salt thereof and one or more of an NS5a inhibitor and/or anNS5b inhibitor is provided. In certain embodiments, pharmaceuticalcompositions are provided which includes a compound I Form and one ormore additional antiviral agents, wherein the additional antiviral agentis not an interferon, ribavirin, or a ribavirin analogue. In furtherembodiments, pharmaceutical compositions is provided which includes aCompound I Form (such as Forms I-XXI), and one or more additionalantiviral agents, wherein the additional antiviral agent is notribavirin or a ribavirin analogue.

In certain embodiments, the compounds disclosed herein are combined withone or more other active ingredients (e.g., one or more additionalantiviral agents) in a unitary dosage form for simultaneous orsequential administration to a patient. The combination therapy may beadministered as a simultaneous or sequential regimen. When administeredsequentially, the combination is administered in two or moreadministrations. In certain embodiments, the active ingredients are: (1)co-formulated and administered or delivered simultaneously in a combinedpharmaceutical composition; (2) delivered by alternation or in parallelas separate pharmaceutical composition; or (3) by some other regimen.When delivered in alternation therapy, the active ingredients areadministered or delivered sequentially, e.g., in separate tablets, pillsor capsules, or by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e. serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

Exemplary inferferons include, without limitation, pegylated rIFN-alpha2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b(Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18,Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1(Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3(Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omegaDUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL,BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005),PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), orbelerofon, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha,infergen, rebif, pegylated IFN-beta, oral interferon alpha, feron,reaferon, intermax alpha, r-IFN-beta, and infergen+actimmune.

Exemplary ribavarin analogs include, without limitation, ribavirin(Rebetol, Copegus), levovirin VX-497, and taribavirin (Viramidine).

Exemplary NS5A inhibitors include, without limitation, ledipasvir(GS-5885), GS-5816, JNJ-47910382, daclatasvir (BMS-790052), ABT-267,MK-8742, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102, A-831, A-689,AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052. For example, NS5Ainhibitors may be found in U.S. Pat. No. 8,575,135, which patent isincorporated by reference.

Exemplary NS5B inhibitors include, without limitation, polymeraseinhibitor is sofosbuvir (GS-7977), tegobuvir (GS-9190), GS-9669,TMC647055, ABT-333, ABT-072, setrobuvir (ANA-598), filibuvir(PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127,valopicitabine (NM-283), R1626, PSI-6130 (R1656), PSI-7851, BCX-4678,nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759,GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837,GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, and BILB-1941.In another embodiment, compounds as described herein may be combinedwith both an NS5A inhibitor and an NS5B inhibitor as describedhereinabove.

Exemplary NS3 protease inhibitors include, without limitation, GS-9451,GS-9256, simeprevir (TMC-435), ABT-450, boceprevir (SCH-503034),narlaprevir (SCH-900518), vaniprevir (MK-7009), MK-5172, danoprevir(ITMN-191), sovaprevir (ACH-1625), neceprevir (ACH-2684), Telaprevir(VX-950), VX-813, VX-500, faldaprevir (BI-201335), asunaprevir(BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, BILN-2065, andBILN-2061.

Exemplary alpha-glucosidase 1 inhibitors include, without limitation,celgosivir (MX-3253), Miglitol, and UT-231B.

Exemplary hepatoprotectants include, without limitation, IDN-6556, ME3738, MitoQ, and LB-84451.

Exemplary non-nucleoside inhibitors of HCV include, without limitation,benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, andphenylalanine derivatives.

Exemplary nucleoside analogues include, without limitation, ribavirin,viramidine, levovirin, a L-nucleoside, or isatoribine and saidinterferon is α-interferon or pegylated interferon.

Exemplary other drugs for treating HCV infection include, withoutlimitation, imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848(DSP-3025), PF-04878691, and SM-360320, cyclophillin inhibitors (e.g.,DEBIO-025, SCY-635, or NIM811) or HCV IRES inhibitors (e.g., MCI-067);emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin, or MitoQ.BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, androxythromycin.

Additional exemplary other drugs for treating HCV infection include,without limitation, zadaxin, nitazoxanide (alinea), BIVN-401 (virostat),DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17,KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975(isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811.

Still further exemplary other drugs for treating HCV infection include,without limitation, thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon(CPG-10101), GS-9525, KRN-tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065,BMS-650032, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, VX-497(merimepodib), DEBIO-025, ANA-975 (isatoribine), XTL-6865, or NIMBI 1.

EXAMPLES Example 1 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethanol solvate (Compound I Form I)

The solution containing Compound I, prepared as discussed in Example 36,was solvent swapped into 7 volumes (7× the mass of Compound I used inequivalent mL volume) ethanol and heated to about 55° C. Then, 3.5volumes of water were added to the solution over about 2 hours at about55° C. Another 2 volumes of water at about 55° C. were added to thesolution. The slurry was cooled to about 20° C. over about 2 hours, agedfor about 5 hours, then filtered and washed with 2 volumes ofethanol/water (1:1 vol/vol) to provide Compound I Form I.

The XRPD pattern for Compound I Form I is shown in FIG. 1 and majorpeaks and their related intensities in the XRPD pattern are shown inTable 1 below.

TABLE 1 Major Peaks in the XRPD Pattern for Compound I Form I Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 15.4674 5.72892 100 11.1347 7.946584.64 12.9258 6.84913 82.94 8.6318 10.24425 66.31

The differential scanning calorimetry (DSC) curve of Form I is shown inFIG. 2. The thermogravimetric analysis (TGA) of Form I comprising athermogram is shown in FIG. 3. The dynamic vapor sorption (DVS) of FormI is shown in FIG. 4. The nuclear magnetic resonance spectrum (¹H NMR)of Form I is shown in shown in FIG. 5.

Example 2 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideethyl acetate solvate (Compound I Form II)

The solution containing Compound I, prepared as discussed in Example 36,was solvent swapped into 5 volumes of EtOAc and heated to about 50° C.Then, 3 volumes of heptane were added at about 50° C. 7 volumes ofheptane were then added to the reactor over about 1 hour at about 50° C.The reactor contents were then cooled to room temperature over about 2hours and the solids were filtered off to provide Form II.

The XRPD pattern for Form II is as shown in FIG. 6. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 2below.

TABLE 2 Major Peaks in the XRPD Pattern for Compound I Form II Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 13.0341 6.79247 100 17.367 5.1063581.26 8.7099 10.15261 76.12 15.3765 5.76261 44.59

The differential scanning calorimetry (DSC) curve of Form II is shown inFIG. 7. The thermogravimetric analysis (TGA) of Form II comprising athermogram is shown in FIG. 8. The nuclear magnetic resonance spectrum(¹H NMR) of Form II is shown in FIG. 9. The dynamic vapor sorption (DVS)of Form II is shown in FIG. 10. Single crystal analysis of Form II isshown in FIG. 11, which shows that there is 1 molar equivalent of ethylacetate for every molecule of Compound I. The unit cell dimensions aregiven below.

Crystal system Monoclinic Space group P2₁ Unit cell dimensions a =11.7472(2) Å b = 10.1096(3) Å c = 20.3398(3) Å α = 90° β = 93.3766(16)°γ = 90°

Example 3 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideisopropanol solvate (Compound I Form III)

Compound I Form III was prepared by adding ˜50 mg of Compound I,prepared as discussed in Example 36, into a vial containing 1 mL ofisopropanol and a magnetic stirrer. The contents of the vial werestirred at room temperature for about ˜48 hours before the wet solidswere isolated to provide Form III.

The XRPD pattern for Form III is as shown in FIG. 12. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 3below.

TABLE 3 Major Peaks in the XRPD Pattern for Compound I Form III Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 11.1013 7.97035 100 15.4961 5.718498.22 19.724 4.50116 44.08 12.7972 6.91768 41.06

The differential scanning calorimetry (DSC) curve of Form III is shownin FIG. 13. The thermogravimetric analysis (TGA) of Form III comprisinga thermogram is shown in FIG. 14. The nuclear magnetic resonancespectrum (¹H NMR) of Form III is shown in FIG. 15. The dynamic vaporsorption (DVS) of Form III is shown in FIG. 16.

Example 4 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedihydrate (Compound I Form IV)

Compound I Form IV was prepared by placing Compound I Form I of Example1 in an accelerated stability chamber set at about 40° C. and 75% R.H.for 2 weeks. After 2 weeks, Form IV was isolated and analyzed.

The XRPD pattern for Form IV is as shown in FIG. 17. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 4below.

TABLE 4 Major Peaks in the XRPD Pattern for Compound I Form IV Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 16.0321 5.5284 100 8.9039 9.9318261.9 8.6774 10.19058 60.64 13.0132 6.80335 53.85

The differential scanning calorimetry (DSC) curve of Form IV is shown inFIG. 18. The thermogravimetric analysis (TGA) of Form IV comprising athermogram is shown in FIG. 19. The dynamic vapor sorption (DVS) of FormIV is shown in FIG. 20. The nuclear magnetic resonance spectrum (¹H NMR)of Form IV is shown in FIG. 21.

Example 5 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemethanol solvate (Compound I Form V)

Compound I Form V was prepared by mixing 400 mg of Compound I, preparedas discussed in Example 36, in an amber vial containing 4 mL of MeOH atroom temperature using a magnetic stir bar. The initial solids dissolvedand re-crystallized out to provide Compound I Form V.

The XRPD pattern for Form V is as shown in FIG. 22. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 5below.

TABLE 5 Major Peaks in the XRPD Pattern for Compound I Form V Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 12.4162 7.12909 100 13.6778 6.474212.63 19.5695 4.53633 8.78 6.2238 14.20129 5.36

The differential scanning calorimetry (DSC) curve of Form V is shown inFIG. 23. The thermogravimetric analysis (TGA) of Form V comprising athermogram is shown in FIG. 24. The dynamic vapor sorption (DVS) of FormV is shown in FIG. 25. Single crystal analysis of Form V is shown inFIG. 26, which shows that there are from about >1 to about 2.5equivalents of methanol for every molecule of Compound I. The unit celldimensions are given in Table 6 below.

TABLE 6 Compound I Form V Unit Cell Information Crystal System:Triclinic Space Group: P1 Volume: 2435.18(19) Å³ Unit Cell Dimensions: a= 10.7741(5) Å b = 15.1017(7) Å c = 15.6272(7) Å α = 82.914(2)° β =89.448(2)° γ = 74.877(2)°

Example 6 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VI)

Compound I Form VI was prepared by placing Compound I Form V in the TGAand heating the sample to about 70° C. and then cooling it back to roomtemperature. After being heated to about 70° C., the sample convertedfrom Form V to Form VI.

The XRPD pattern for Form VI is as shown in FIG. 27. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 7below.

TABLE 7 Major Peaks in the XRPD Pattern for Compound I Form VI Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 14.6141 6.06146 100 15.4028 5.752869.18 20.0345 4.43207 64.15 18.0922 4.90327 62.51

The differential scanning calorimetry (DSC) curve of Form VI is shown inFIG. 28. The thermogravimetric analysis (TGA) of Form VI comprising athermogram is shown in FIG. 29. The dynamic vapor sorption (DVS) of FormVI is shown in FIG. 30.

Example 7 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VII)

Compound I Form VII was prepared by heating Compound I Form I to about240° C. or heating Compound I Form V to about 220° C. or heatingCompound I Form IX to about 200° C.

The XRPD pattern for Form VII is as shown in FIG. 31. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 8below.

TABLE 8 Major Peaks in the XRPD Pattern for Compound I Form VII Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 18.663 4.75458 100 6.5242 13.5480295.36 8.527 10.36991 78.68 17.5074 5.06571 35.36

The differential scanning calorimetry (DSC) curve of Form VII is shownin FIG. 32. The nuclear magnetic resonance spectrum (¹H NMR) of Form VIIis shown in FIG. 33. The thermogravimetric analysis (TGA) of Form VIIcomprising a thermogram is shown in FIG. 34. The dynamic vapor sorption(DVS) of Form VII is shown in FIG. 35.

Example 8 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form VIII)

Compound I Form VIII was prepared by charging 0.1 g of Compound I FormVI into a 25 mL round bottom flask with a magnetic stir bar. 5 mL ofwater was charged into the flask, which was then heated to about 85° C.Next, 1 g of Compound I Form V was charged into the flask. 5 mL ofacetone water (1:4 vol./vol.) was used to wash the solids on the innerside of the flask. The contents of the flask were held at about 85° C.overnight. The next day, the contents of the flask were then cooled toroom temperature and held at room temperature for another night. Thesolids were filtered out and analyzed to indicate that both Forms V andVI converted to a new form, Form VIII.

The XRPD pattern for Form VIII is as shown in FIG. 36. Major peaks andtheir related intensities in the XRPD pattern are shown in Table 9below.

TABLE 9 Major Peaks in the XRPD Pattern for Compound I Form VIII Pos.[°2Th.] d-spacing [Å] Rel. Int. [%] 7.7598 11.39333 100 8.2313 10.7417350.21 20.1662 4.40343 43.56 16.4818 5.37855 41.17

The differential scanning calorimetry (DSC) curve of Form VIII is shownin FIG. 37. The thermogravimetric analysis (TGA) of Form VIII comprisinga thermogram is shown in FIG. 38. The dynamic vapor sorption (DVS) ofForm VIII is shown in FIG. 39.

Example 9 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(anhydrous, Compound I Form IX)

Compound I Form IX was prepared by charging Compound I Form VI intocontainer, to which 10 volumes of 1:1 heptane/toluene was added and themixture heated and slurried at 60° C. overnight. The mixture was thenfiltered directly without cooling and the product was dried at about 50°C. under vacuum.

The XRPD pattern for Form IX is as shown in FIG. 40. The differentialscanning calorimetry (DSC) curve of Form IX is shown in FIG. 41. Thethermogravimetric analysis (TGA) of Form IX comprising a thermogram isshown in FIG. 42. The dynamic vapor sorption (DVS) of Form IX is shownin FIG. 43.

Example 10 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidehemihydrate (Compound I Form X)

Compound I Form X was prepared by slurring Compound I Form VIII in waterat about 80° C.

The XRPD pattern for Form X is as shown in FIG. 44. The differentialscanning calorimetry (DSC) curve of Form X is shown in FIG. 45. Thethermogravimetric analysis (TGA) of Form X comprising a thermogram isshown in FIG. 46. The dynamic vapor sorption (DVS) of Form X is shown inFIG. 47.

Example 11 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedihydrate (Compound I Form XI)

Compound I Form XI was prepared by slurring a mixture of Compound I FormIV and Compound I Form X in 7:3 (v/v) ethanol:water.

The XRPD pattern for Form XI is as shown in FIG. 48. The differentialscanning calorimetry (DSC) curve of Form XI is shown in FIG. 49. Thethermogravimetric analysis (TGA) of Form XI comprising a thermogram isshown in FIG. 50. The dynamic vapor sorption (DVS) of Form XI is shownin FIG. 51.

Example 12 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidetetrahydrate (Compound I Form XII)

Compound I Form XII was prepared by dissolving Compound I amorphousmaterial in 1:1 acetone:water and then sonicating the solution for about1 hour.

The XRPD pattern for Form XII is as shown in FIG. 52. The differentialscanning calorimetry (DSC) curve of Form XII is shown in FIG. 53. Thethermogravimetric analysis (TGA) of Form XII comprising a thermogram isshown in FIG. 54. The dynamic vapor sorption (DVS) of Form XII is shownin FIG. 55.

Example 13 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XIII)

Compound I Form XIII was prepared by slurring Compound I amorphousmaterial in isopropyl acetate at room temperature.

The XRPD pattern for Form XIII is as shown in FIG. 56. The differentialscanning calorimetry (DSC) curve of Form XIII is shown in FIG. 57. Thethermogravimetric analysis (TGA) of Form XIII comprising a thermogram isshown in FIG. 58. The dynamic vapor sorption (DVS) of Form XIII is shownin FIG. 59.

Example 14 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XIV)

Compound I Form XIV was prepared by slurring Compound I amorphousmaterial in 3:7 (v/v) THF:water at room temperature.

The XRPD pattern for Form XIV is as shown in FIG. 60. The differentialscanning calorimetry (DSC) curve of Form XIV is shown in FIG. 61. Thethermogravimetric analysis (TGA) of Form XIV comprising a thermogram isshown in FIG. 62. The dynamic vapor sorption (DVS) of Form XIV is shownin FIG. 63.

Example 15 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XV)

Compound I Form XV was prepared by slurring Compound I amorphousmaterial in 2-Me-THF at room temperature.

The XRPD pattern for Form XV is as shown in FIG. 64. The differentialscanning calorimetry (DSC) curve of Form XV is shown in FIG. 65. Thethermogravimetric analysis (TGA) of Form XV comprising a thermogram isshown in FIG. 66. The dynamic vapor sorption (DVS) of Form XV is shownin FIG. 67.

Example 16 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XVI)

Compound I Form XVI was prepared by slurring Compound I Form VIII in 4:1(v/v) toluene:heptane.

The XRPD pattern for Form XVI is as shown in FIG. 68. The differentialscanning calorimetry (DSC) curve of Form XVI is shown in FIG. 69. Thethermogravimetric analysis (TGA) of Form XVI comprising a thermogram isshown in FIG. 70.

Example 17 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XVII)

Compound I Form XVII was prepared by slurring Compound I amorphousmaterial in toluene at room temperature.

The XRPD pattern for Form XVII is as shown in FIG. 71. The differentialscanning calorimetry (DSC) curve of Form XVII is shown in FIG. 72. Thethermogravimetric analysis (TGA) of Form XVII comprising a thermogram isshown in FIG. 73.

Example 18 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XVIII)

Compound I Form XVIII was prepared by slurring Compound I amorphousmaterial in MTBE at room temperature.

The XRPD pattern for Form XVIII is as shown in FIG. 74. The differentialscanning calorimetry (DSC) curve of Form XVIII is shown in FIG. 75. Thethermogravimetric analysis (TGA) of Form XVIII comprising a thermogramis shown in FIG. 76. The dynamic vapor sorption (DVS) of Form XVIII isshown in FIG. 77.

Example 19 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XIX)

Compound I Form XIX was prepared by crystallizing Compound I from 1:4(v/v) MTBE:n-heptane.

The XRPD pattern for Form XIX is as shown in FIG. 78. The differentialscanning calorimetry (DSC) curve of Form XIX is shown in FIG. 79. Thethermogravimetric analysis (TGA) of Form XIX comprising a thermogram isshown in FIG. 80.

Example 20 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XX)

Compound I Form XX was prepared by dissolving Compound I Form VIII inDMAc and allowing the sample to evaporate to dryness.

The XRPD pattern for Form XX is as shown in FIG. 81. The differentialscanning calorimetry (DSC) curve of Form XX is shown in FIG. 82. Thethermogravimetric analysis (TGA) of Form XX comprising a thermogram isshown in FIG. 83. The dynamic vapor sorption (DVS) of Form XX is shownin FIG. 84.

Example 21 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesolvate (Compound I Form XXI)

Compound I Form XXI was prepared by dissolving Compound I Form VIII inDMF and allowing the sample to evaporate to dryness.

The XRPD pattern for Form XXI is as shown in FIG. 85. The differentialscanning calorimetry (DSC) curve of Form XXI is shown in FIG. 86. Thethermogravimetric analysis (TGA) of Form XXI comprising a thermogram isshown in FIG. 87. The dynamic vapor sorption (DVS) of Form XXI is shownin FIG. 88.

Example 22 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form I)

Compound I sodium Form I was prepared by slurring a mixture of CompoundI sodium Form I and Compound I sodium Form II in ethanol.

The XRPD pattern for Compound I sodium Form I is as shown in FIG. 89.The differential scanning calorimetry (DSC) curve of Compound I sodiumForm I is shown in FIG. 90. The thermogravimetric analysis (TGA) ofCompound I sodium Form I comprising a thermogram is shown in FIG. 91.The dynamic vapor sorption (DVS) of Compound I sodium Form I is shown inFIG. 92.

Example 23 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form II)

Compound I sodium Form II was prepared by exposing Compound I sodiumForm I to relative humidity conditions less that 40% RH.

The XRPD pattern for Compound I sodium Form II is as shown in FIG. 93.The differential scanning calorimetry (DSC) curve of Compound I sodiumForm II is shown in FIG. 94. The thermogravimetric analysis (TGA) ofCompound I sodium Form II comprising a thermogram is shown in FIG. 95.The dynamic vapor sorption (DVS) of Compound I sodium Form II is shownin FIG. 96.

Example 24 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form III)

Compound I sodium Form III was prepared by slurring a mixture ofCompound I sodium Form I and Compound I sodium Form II in either IPA,EtOAc, acetone, THF, or MEK.

The XRPD pattern for Compound I sodium Form III is as shown in FIG. 97.The differential scanning calorimetry (DSC) curve of Compound I sodiumForm III is shown in FIG. 98. The thermogravimetric analysis (TGA) ofCompound I sodium Form III comprising a thermogram is shown in FIG. 99.The dynamic vapor sorption (DVS) of Compound I sodium Form III is shownin FIG. 100.

Example 25 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidesodium (Compound I sodium Form IV)

Compound I sodium Form IV was prepared by slurring a mixture of CompoundI sodium Form I and Compound I sodium Form II in either IPAc or MIBK.

The XRPD pattern for Compound I sodium Form IV is as shown in FIG. 101.The differential scanning calorimetry (DSC) curve of Compound I sodiumForm IV is shown in FIG. 102. The thermogravimetric analysis (TGA) ofCompound I sodium Form IV comprising a thermogram is shown in FIG. 103.The dynamic vapor sorption (DVS) of Compound I sodium Form IV is shownin FIG. 104.

Example 26 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidemeglumine (Compound I meglumine Form I)

Compound I meglumine Form I was prepared by cooling a solution ofCompound I with meglumine in 1:1 (v/v) toluene:heptane from elevatedtemperature followed by vacuum drying at elevated temperature.

The XRPD pattern for Compound I meglumine Form I is as shown in FIG.105. The differential scanning calorimetry (DSC) curve of Compound Imeglumine Form I is shown in FIG. 106. The thermogravimetric analysis(TGA) of Compound I meglumine Form I comprising a thermogram is shown inFIG. 107.

Example 27 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepiperazine (Compound I piperazine Form I)

Compound I piperazine Form I was prepared by cooling a solution ofCompound I with piperazine in 1:1 (v/v) ethanol:water from elevatedtemperature.

The XRPD pattern for Compound I piperazine Form I is as shown in FIG.108. The differential scanning calorimetry (DSC) curve of Compound Ipiperazine Form I is shown in FIG. 109. The thermogravimetric analysis(TGA) of Compound I piperazine Form I comprising a thermogram is shownin FIG. 110.

Example 28 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidecholine (Compound I choline Form I)

Compound I choline Form I was prepared by cooling a solution of CompoundI with choline in 1:1 (v/v) toluene:heptane from elevated temperaturefollowed by vacuum drying at elevated temperature.

The XRPD pattern for Compound I choline Form I is as shown in FIG. 111.The differential scanning calorimetry (DSC) curve of Compound I cholineForm I is shown in FIG. 112. The thermogravimetric analysis (TGA) ofCompound I choline Form I comprising a thermogram is shown in FIG. 113.

Example 29 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidedeanol (Compound I deanol Form I)

Compound I deanol Form I was prepared by slurring Compound I with deanolin 1:1 (v/v) toluene:heptane at elevated temperature.

The XRPD pattern for Compound I deanol Form I is as shown in FIG. 114.

Example 30 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyetthyl)-pyrrolidine (Compound I1-(2-hydroxyetthyl)-pyrrolidine Form I)

Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form I was prepared bycooling a solution of Compound I with pyrrolidine in 18:83 (v/v) ethylacetate:methanol from elevated temperature with volume reduction.

The XRPD pattern for Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form Iis as shown in FIG. 115. The differential scanning calorimetry (DSC)curve of Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form I is shown inFIG. 116. The thermogravimetric analysis (TGA) of Compound I1-(2-hydroxyetthyl)-pyrrolidine Form I comprising a thermogram is shownin FIG. 117.

Example 31 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyetthyl)-pyrrolidine (Compound I1-(2-hydroxyetthyl)-pyrrolidine Form II)

Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form II was prepared byvacuum drying Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form I at about80° C.

The XRPD pattern for Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form IIis as shown in FIG. 118.

Example 32 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide1-(2-hydroxyetthyl)-pyrrolidine (Compound I1-(2-hydroxyetthyl)-pyrrolidine Form III)

Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form III was prepared byevaporation of a solution of Compound I with pyrrolidine from 1:1 (v/v)methyl-tert-butyl ether:toluene.

The XRPD pattern for Compound I 1-(2-hydroxyetthyl)-pyrrolidine Form IIIis as shown in FIG. 119.

Example 33 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidelysine (Compound I lysine Form I)

Compound I lysine Form I was prepared by cooling of a solution ofCompound I with lysine from 4:1 (v/v) ethanol:water from elevatedtemperature.

The XRPD pattern for Compound I lysine Form I is as shown in FIG. 120.

Example 34 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidearginine (Compound I arginine Form I)

Compound I arginine Form I was prepared by evaporation of a solution ofCompound I with arginine from 4:1 (v/v) isopropanol:water.

The XRPD pattern for Compound I arginine Form I is as shown in FIG. 121.

Example 35 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamidepotassium (Compound I potassium Form I)

Compound I potassium Form I was prepared by dissolving Compound I FormII in ˜10 mL/g of IPA, followed by remove ˜10% of IPA throughdistillation and recharged ˜10% IPA. The solution was then heated toabout 60° C., and 1.5 eq of KOH (aq) was charged and mixture cooled toabout 10° C.

The XRPD pattern for Compound I potassium Form I is as shown in FIG.122. The differential scanning calorimetry (DSC) curve of Compound Ipotassium Form I is shown in FIG. 123. The thermogravimetric analysis(TGA) of Compound I potassium Form I comprising a thermogram is shown inFIG. 124. The dynamic vapor sorption (DVS) of Compound I potassium FormI is shown in FIG. 125.

Example 36 Synthesis of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(I) by route I

Compound of formula I was synthesized via route I as shown below:

Synthesis of Intermediates for Compound of Formula I A. Synthesis ofMethyl (2S,3S,4R)-3-ethyl-4-hydroxypyrrolidine-2-carboxylate TosylateSalt (II)

The order of reduction of the double bond and ketone was reversed so newintermediates were formed, B (R=tBu) and C (R=tBu). The t-butyl esterwas used to make D in U.S. Publication No. 2014-0017198; however, it wasconverted directly to the methyl ester tosylate salt withoutchromatography and crystallized to remove diastereomeric impurities. Asingle crystal X-Ray of the tosylate salt II was obtained.

Step 1: Synthesis of A

I. Enamine Formation to A

DMF-DMA (125.3 g, 2.0 eq.) and DCM (300 mL) were charged to a reactorunder N₂ and heated to 45° C. In a separate container the commerciallyavailable starting material (150 g) was dissolved in DCM (300 mL) underN₂. This solution was charged to the reactor containing the DMF-DMAsolution over 3 hours. Upon reaction completion, the solution was cooledto room temperature. 5% LiCl (750 mL) was added to the reactor and themixture was stirred. The layers were separated and the aqueous layer wasremoved. Water (750 mL) was added to the reactor and the mixture wasstirred. The layers were separated and the aqueous layer was removed.The organic layer was dried with Na₂SO₄ and the mixture was polishfiltered.

The filtrate was concentrated to ˜200 mL and heptane (600 mL) wascharged to obtain a murky solution. The mixture was further concentratedto remove residual DCM. Additional heptane (600 mL) was added and themixture was heated to about 50-60° C. and aged for about 1 h to obtain aslurry. The slurry was cooled to about 15° C. over about 4 hours beforeaging at about 15° C. overnight (˜18 h). Intermediate A (R=tBu) wasisolated via vacuum filtration and rinsed with 2 volumes heptane. Theresulting solid was dried in a vacuum oven at about 45° C. to constantweight to obtain 141.8 g of A (R=tBu). ¹H NMR (400 MHz, CDCl₃) (mixtureof E/Z isomer): δ 7.4 (s, 1H), 5.2-5.3 (s, 1H), 3.8 (d, 2H) 3.2 (broads, 6H), 1.5 (s, 9H), 1.4 (s, 9H). UPLC/MS M+1=341 amu.

Step 2: Synthesis of B (R=tBu)

I. Methylation of A (R=tBu) to B (R=tBu:

To a reaction vessel was added A (151 g, 0.44 mol, 1.0 equiv). Thevessel was evacuated, purged with nitrogen, and the substrate wasdissolved in MeTHF (450 mL, 3 vol). The reaction mixture was cooled toan internal temperature of about −12° C. and treated dropwise withmethylmagnesium bromide (155 mL of a 3.0 M solution in diethyl ether,0.55 mol, 1.25 equiv) over about 1 h. Upon reaction completion (about 2h), a reverse quench was performed by adding the reaction to coldsaturated aqueous ammonium chloride (400 mL). If an emulsion wasobserved, more aqueous ammonium chloride or 2 M HCl was added. Theaqueous layer was extracted with toluene (1×200 mL). The organic layerswere combined, washed with 1 M HCl (150 mL), then brine (150 mL), andconcentrated in vacuo to provide B. ¹H NMR (400 MHz, CDCl₃): δ 6.90-6.92(1H, m), 5.08-5.16 (1H, m), 3.94-4.00 (2H, m), 2.02-2.04 (3H, m),1.44-1.49 (18H, m).

Step 3: Synthesis of C (R=tBu)

I. Hydrogenation of B (R=tBu) to C (R=tBu):

Enone B (R=tBu) (32.0 g, 0.10 mol) was dissolved in toluene (3 vol)under an atmosphere of N₂. Pd/C was subsequently added (1.1 g, 0.5 mol%) and the reaction was flushed with N₂, followed by H₂, and stirredvigorously at room temperature under 1 atm of H₂. After completion ofthe reaction, diatomaceous earth (0.1 S, 13.2 g) was added and themixture was stirred for 5 minutes. The heterogeneous mixture wasfiltered through diatomaceous earth and rinsed with additional toluene(0.5-1 vol) and concentrated to dryness to provide C as a pale yellowsolid. ¹H NMR (400 MHz, CD₃OD): δ 4.68 (dd, J=36.9, 9.3 Hz, 1H),3.99-3.75 (m, 2H), 2.63 (tdd, J=13.7, 9.2, 4.6 Hz, 1H), 1.89 (dt,J=13.8, 6.7 Hz, 1H), 1.46 (s, 9H), 1.43 (s, 9H), 1.30-1.16 (m, 1H), 1.07(t, J=7.4 Hz, 3H). Epi-C has a characteristic peak at 4.23 ppm in MeOD(d, J=3.5 Hz, 1H) which can be used to calculate thediastereoselectivity of the hydrogenation. The diastereoselectivity wasdetermined by NMR to be typically >50:1.

Step 4: Synthesis of D (R=tBu)

I. Reduction of C (R=tBu) to Provide D (R=tBu)

ZnCl₂ (27.3 g, 200 mmol, 2 equiv) and CPME (7 vol relative to C, 220 mL)were combined and the heterogeneous mixture was warmed to an internaltemperature of about 95° C. and stirred for about 1.5 hours at thattemperature. The resulting slurry was cooled to about 25° C. NaBH₄ (7.56g, 200 mmol, 2 equiv) was added and the mixture was stirred overnight(˜18 hrs).

The slurry was cooled to about 0° C., and the solution of C (R=tBu)(˜100 mmol) in toluene (3 total vol) was added slowly while maintainingthe temperature to about below +3° C. After addition, the mixture wasstirred at about 0° C. until complete consumption of the startingmaterial. The reaction was quenched by reverse addition into a solutionof citric acid (2.5 equiv, 48 g) in ice water (200 mL). The layers wereseparated and the organic layer was washed with brine (60 mL, 2 vol),dried over MgSO₄ (0.05 S, 1.5 g), and polish filtered. The crude organicsolution was concentrated to a thick oil, diluted with 2 volumes ofhexanes and filtered through 2S silica gel, eluting with 1:1acetone:hexanes. Concentration in vacuo provided compound of formula D(R=tBu).

¹H NMR (400 MHz, CDCl₃): δ 4.30 (dd, J=26.4, 8.4 Hz, 1H), 4.24-4.14 (m,1H), 3.89 (ddd, J=14.6, 10.6, 7.5 Hz, 1H), 3.15 (ddd, J=17.7, 10.6, 7.1Hz, 1H), 2.20-2.05 (m, 2H), 1.70-1.59 (m, 1H), 1.48 (s, 9H), 1.44 (s,9H), 1.35-1.23 (m, 1H), 1.07 (t, J=7.4 Hz, 3H).

Synthesis of Compound of Formula II (R═CH₃)

Deprotection and Transesterification of D (R=tBu) to II (R═CH₃):

D (R=tBu) (5.55 g, 17.6 mmol) was charged to a reactor and dissolved inmethanol (55.5 mL). p-Toluenesulfonic acid (10.7 g, 3.2 eq.) was chargedto the solution and the mixture is stirred for about 1 hour at roomtemperature. The mixture was then heated to about 60° C. The reactionwas stirred until reaction completion. The reaction mixture wasconcentrated to about 4 volumes and cooled to about 45° C. MTBE (4volumes) were added slowly to achieve a cloudy solution. II seed (0.05%)was charged to the solution to and the mixture was aged for about 30minutes to obtain a thin slurry. Additional MTBE (5 volumes) werecharged over about 90 minutes and the resulting slurry was stirredovernight.

The slurry was filtered and rinsed with 2 volumes of MTBE. The resultingwet cake was dried under vacuum at about 40° C. to obtain compound II(R═CH₃) as a tosylate salt. ¹H NMR (400 MHz, MeOD) δ 7.7 (d, 2H), 7.2(d, 2H), 4.7 (d, 1H), 4.3 (m, 1H), 3.8 (s, 3H), 3.6 (m, 1H), 3.2 (m,1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.3 (m, 2H), 1.0 (t, 3H). LC/MS M+1=174.1

B. Synthesis of3-Chloro-2-(1,1-difluorobut-3-en-1-yl)-6-methoxyquinoxaline (IV)

Compound IV contains one more methylene group than the analog used inU.S. Publication No. 2014-0017198 and so requires a different startingmaterial. Ethyl trifluoropyruvate was converted to intermediate G inthree steps. Intermediate G was telescoped through to a 4:1regioisomeric mixture of J and K. In the U.S. Publication No.2014-0017198, a nitro, amino-anisole was used for the ring formation ina two-step process of reacting the amine first and then reducing thenitro group to allow cyclization. Two regioisomers were formed. In thisroute, the starting material was instead the diamino analog and similarmixture was obtained. The mixture was chlorinated and the desired isomerIV was purified by conventional methods.

Step 1: Synthesis of G

I. Synthesis of Intermediate of Formula G from Ethyl Trifluoropyruvate:

a. Allylation of Ethyl Trifluoropyruvate to Provide E:

To a reaction vessel was charged ethyl trifluoropyruvate (86 g, 0.5056mol, 1.0 equivalent) and dichloromethane (260 mL). Allyl alcohol (31 g,0.5337 mol, 1.1 equivalent) was charged dropwise over about 30 minuteswhile maintaining the reaction temperature less than about 27° C. Thereaction was cooled to about 5° C. and pyridine (123 mL, 1.52 mol, 3.0equivalents) was charged over about 50 minutes, maintaining a reactiontemperature below about 8° C., followed by charging thionyl chloride (90g, 0.76 mol, 1.5 equivalents) over about 90 minutes while maintainingthe reaction temperature below about 12° C. The reaction was stirred forabout 30 minutes at about 5 to 10° C., warmed to about 22° C. over about30 minutes and held at about 22° C. until the reaction was deemedcomplete. The reaction mixture was poured into 860 mL of chilled (about8° C.) water and the phases separated. The aqueous phase wasback-extracted with 200 mL dichloromethane. The combined dichloromethanephases were washed successively with water (860 mL), 5 wt % NaHCO₃solution (2×250 mL), and a final water wash (250 mL) and dried overNa₂SO₄. After the removal of the solvents, the crude product E wasisolated and used directly for the next step. ¹H NMR (300 MHz, CDCl₃): δ5.92 (m, 1H), 5.38 (dq, J=14.1, 1.4 Hz, 1H), 5.27 (dq, J=10.3, 1.2 Hz,1H), 4.40 (d, J=7.1 Hz, 2H), 4.34 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

II. Zn-Mediated Elimination of ClF from E to Provide F Followed byClaisen to Provide G:

To a reaction vessel was charged zinc powder (324 g, 4.95 mol, 2.0equivalents), CuI (6 g, 0.032 mmol, 0.013 equivalents) andN,N-dimethylformamide (DMF) (3.0 L). The mixture was stirred vigorouslyas Me₃SiCl (309 mL, 2.43 mmol, 1.0 equivalents) was charged dropwise viaaddition funnel over about 10 minutes, maintaining the reactiontemperature at about <25° C. The reaction was stirred for about 30minutes at about 25° C. The reaction was then cooled to about 0 to 5° C.over about 20 minutes and a solution of compound E (600 g, 2.43 mol, 1.0equivalents) in DMF (3.0 L) was added slowly over about 60 minutes,maintaining the reaction temperature about <10° C. The reaction wasstirred for about 30 minutes at 5 to 10° C., warmed to about 22° C. overabout 30 minutes and then held at about 22° C. until the reaction wasdeemed complete by ¹⁹F NMR (typically 1-2 hours).

III. Claisen Rearrangement of F to Provide G

The above reaction mixture was filtered and washed with ethyl acetate(2×3 L). Water (1.5 L) was added to the organic phase and the layerswere separated. The organic layer was washed two additional portions ofwater (2×1.5 L). The organic solution was concentrated to obtain crudeF. This was dissolved in 3.0 L (5 volumes) of toluene and heated toabout 80° C. until the reaction was deemed complete (typically 1-3 h).The reaction was cooled to about 22° C. and the solvent removed viarotary evaporation to obtain the crude product G (˜70 wt %)). ¹H NMR(300 MHz, CDCl₃): δ 5.90 (m, 1H), 5.28 (m, 2H), 4.40 (q, J=7.1 Hz, 2H),2.83 (dt, J=18.5, 7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); ¹⁹F NMR (CDCl₃) δ−112.8 (t).

Step 2: Synthesis of H

I. Synthesis of H from G

To a reaction flask e was charged G (26.2 g, 136.6 mmol, 1.0 equivalent)and THF (236 mL, 9 vol.). Water (52 mL, 2 vol.) was charged followed byLiOH.H₂O (14.9 g, 354.5 mmol, 2.6 equiv.) maintaining a reactiontemperature below about 33° C. The reaction was held at about 22° C. forabout 3 hours followed by quenching with 250 mL of 1M HCl. The pH wasthen adjusted to 3 by addition of 20 mL of concentrated HCl. The phaseswere separated and the aqueous phase was back-extracted with 260 mL ofmethyl-t-butyl ether. The layers were split and 52 grams of NaCl wasadded to the aqueous phase which was extracted with 2×130 mL of MTBEfollowed by 50 mL of EtOAc. All the organic phases were combined anddried over Na₂SO₄, filtered, concentrated and dried under vacuum toobtain H). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 6.92 (br s, 2H),5.83-5.70 (m, 1H), 5.20-5.13 (m, 2H), 2.83-2.65 (m, 2H). ¹⁹F-NMR(DMSO-d₆) δ −88.20 (t, J=20.8 Hz). TLC (Silica gel, 4:1 EtOAc:heptane,visualization with KMnO₄ stain) Rf=0.50.

Step 3: Synthesis of J

I. Condensation Followed by Cyclization to Provide J from H:

To a reaction vessel was charged diamine (6.06 g, 28.7 mmol, 1.0equivalent) and ethanol (130 mL). Triethylamine (8.8 mL, 63.1 mol, 2.2equivalents) was charged over about 5 minutes maintaining the reactiontemperature about <25° C. The reaction was agitated for about 10 minutesuntil complete dissolution of the slurry to a homogenous solution.Acetic acid (16.4 mL, 287 mmol, 10 equiv.) followed by a solution of H(5.75 g, 31.6 mmol, 1.1 equiv.) in ethanol (40 mL) was charged and thereaction was held at about 22° C. until the reaction was complete. Thereaction mixture was solvent exchanged into 80 mL of dichloromethane andwashed successively with 0.1 N HCl (60 mL), saturated NaHCO₃ solution(60 mL) and a final brine wash (60 mL) and dried over Na₂SO₄. After theremoval of the solvents, crude mixture of J/K was obtained. This crudemixture was dissolved in dichloromethane, washed twice with 0.1N HCl,once with water and once with brine followed by drying over sodiumsulfate, filtered and concentrated to obtain J/K). ¹H NMR (300 MHz,CDCl₃): δ 7.82 (d, J=9.0 Hz, 1H), 7.38 (m, 1H), 6.97 (dd, J=9.0, 3.0 Hz,1H), 6.82 (d, J=3.0 Hz, 1H), 5.88 (m, 1H), 5.22 (m, 2H), 3.91 (s, 3H),3.28 (td, J=12.0, 3.0 Hz, 2H). ¹⁹F NMR (282.2 MHz, CDCl₃): δ −100.3 ppm(J) and −100.8 ppm (K). LCMS: m/z=266.93.

Step 4: Synthesis of IV

I. Chlorination of J to Provide Compound of Formula IV:

To a reaction vessel was charged J (7.4 g, 27.79 mmol, 1.0 equivalent)and N,N-dimethylformamide (148 mL). Phosphorus oxychloride (POCl₃) (4.2mL, 44.47 m mol, 1.6 equivalent) was charged over about 3 minutesmaintaining the reaction temperature was kept below about 30° C. Thereaction was heated to about 75° C. until reaction completion. Thereaction mixture was slowly poured into 150 mL of water whilemaintaining the temperature below about 25° C. Methyl-t-butyl ether(MTBE) (75 mL) was charged and the phases separated. The aqueous phasewas back-extracted with 4×75 mL of MTBE. The combined MTBE phases werewashed successively with saturated NaHCO₃ solution (200 mL) andsaturated NaCl solution (150 mL) and dried over Na₂SO₄. After theremoval of the solvents, the crude product IV was isolated. The crudematerial was suspended in hexanes (4.3 volumes), heated to dissolutionand slowly cooled to about 20° C. resulting in slurry formation of thedesired regioisomer IV which was then isolated by filtration and dried.¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H), 7.48 (dd, J=9.0, 3.0Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 5.97 (m, 1H), 5.31 (m, 2H), 4.0 (s,3H), 3.35 (td, J=12.0, 3.0 Hz, 2H). ¹⁹F NMR (282.2 MHz, CDCl₃): δ −96.3ppm (IV) and −97.1 ppm (regioisomer). LCMS: m/z=285.27.

C. Synthesis of(S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutanoicacid (S)-1-Phenylethan-1-amine Salt (VII)

Compound of formula VII contains one less methylene than the materialused in the medicinal chemistry route in order to shift the ring-closingmetathesis reaction away from the difluorinated methylene on thequinoxaline fragment. A similar Kulinkovich cyclopropanation, acylationand enzymatic resolution was used with this homolog. The cyclopropanoland then cyclopropyl acetate were distilled but it was not necessary todo so. Acid-base extractions were used to remove still acetylatedmaterial. The final product was isolated as a S-1-phenylethanamine saltwhich improved the diastereomeric and overall purity of the product.Recrystallization may be used to further improve the purity of theproduct. Other salts may be possible.

Step 1: Synthesis of (1R,2R)-2-allylcyclopropan-1-ol (M1)

Kulinkovich Reaction, Acetylation and Enzymatic Resolution:

I. Kulinkovich Reaction with Ethyl Formate and 5-Bromo-1-Pentene

To a reaction vessel was added magnesium turnings (2.45 equivalents) andMeTHF (8 volumes). The flask was then sparged with nitrogen and5-bromo-1-pentene (2.4 equivalents) was added to the addition funnel.The mixture was heated to about 60° C. and 0.05 volumes of5-bromo-1-pentene were dripped into the mixture to initiate thereaction. Once the reaction initiated, the remaining portion of5-bromo-1-pentene was slowly added into the flask over about 3 hours.After the addition, the reaction was allowed to stir at about 60° C. forabout 1 hour after which Grignard L was cooled to room temperature. In aseparate flask was added ethyl formate (1.0 equivalent) and titaniumisopropoxide (0.5 equivalents) in MeTHF (2 volumes) under nitrogen. Themixture was cooled to about 0° C. and slowly the Grignard L was addedinto the flask over 3 hours. Upon complete addition, the reactionmixture was allowed to warm to room temperature and the reaction wasstirred for about 12 hours. The mixture was then cooled to about 0° C.and 4M sulfuric acid (10 volumes) was added slowly. The slurry wasstirred for 30 minutes after which the salts were dissolved. The mixturewas then polished filtered. The biphasic mixture was separated and theorganic layer was then washed twice with 10 wt. % sodium bicarbonate (10volumes) and once with water (10 volumes). The organic layer isconcentrated under reduced pressure at about 0° C. to obtain crude2-allylcyclopentanol M. ¹H NMR (400 MHz, CDCl₃): δ 5.53-5.43 (m, 1H),4.76-4.70 (m, 1H), 4.65-4.59 (m, 1H), 2.90-2.86 (m, 1H), 1.75 (br s,1H), 1.65-1.51 (m, 2H), 0.69-0.59 (m, 1H), 0.40-0.35 (m, 1H), 0.05-0.01(m, 1H).

II. Acetylation of 2-allylcyclopentanol (+/−)-M:

Into a reaction vessel was added 2-allylcyclopentanol M (1 equivalent)in MeTHF (10 volumes). The vessel was purged with nitrogen and thesolution was then cooled to 0° C. Triethylamine (3.0 equivalents) wasthen slowly added to the solution over about 30 minutes. The mixture wasallowed to stir for about 30 minutes after which acetyl chloride (2.5equivalents) was added maintaining the internal temperature about below20° C. The reaction was then allowed to stir for at least 12 hours atabout 21° C. After the allotted time, water (6 volumes) was slowlycharged to the reactor and the phases were separated. The organic layerwas then washed with 2M hydrochloric acid (6 volumes), 10 wt. % sodiumbicarbonate (6 volumes) and then brine (6 volumes). The organic layer isconcentrated under reduced pressure at about 0° C. to obtain cruderacemic 2-allylcyclopropyl acetate N. ¹H NMR (400 MHz, CDCl₃): δ5.85-5.73 (m, 1H), 5.10-5.04 (m, 1H), 5.00-4.97 (m, 1H), 3.85-3.82 (m,1H), 2.13-2.07 (m, 1H), 1.99 (s, 3H), 2.01-1.89 (m, 1H), 1.14-1.03 (m,1H), 0.87-0.76 (m, 1H), 0.64-0.57 (m, 1H).

III. Enzymatic Resolution of 2-Allylcyclopentanol

To a reaction vessel was charged 2-allylcyclopropyl acetate N in MeTHF(2 volumes) and MTBE phosphate buffer solution (10 volumes). The MTBEphosphate buffer solution was prepared by first dissolving potassiumphosphate dibasic (283 g) and potassium phosphate monobasic (104.8 g) inwater (1.6 L). MTBE (800 mL) was added to the solution and the biphasicmixture was stirred at about 21° C. for about 1 hour. The organic layerwas then separated and used as the MTBE phosphate buffer solution. Thereaction mixture was then cooled to about 0° C. and solid supportedNovozyme 435 (1.7 wt. %) was charged. The reaction was allowed to stirat about 0° C. for about 6 hours after which the mixture was filtered.The filtrate was then concentrated under reduced pressure at about 0° C.to obtain the majority as (1R,2R)-2-allylcyclopropan-1-ol M1 and theracemic (1S,2S)-2-allylcyclopropan-1-ol in a 10:1 to 15:1 mixture as amixture of the corresponding remaining acylated starting materials. Thecrude mixture was carried forward as is.

Step 3: Synthesis of VII

I. Coupling to VII

A solution of alcohol M1 in MTBE and MeTHF (contains 14 g of desiredalcohol) was charged to a reactor. DMF (140 mL) and N,N′-disuccinimidylcarbonate (47.5 g, 1.3 eq) were charged to the reactor to obtain a thinslurry. Pyridine (11.3 g, 1 eq) was charged and the reaction mixture washeated to about 45° C. Upon reaction completion, the reaction mixturewas cooled to about 0° C. and quenched with water (196 mL). The reactionmixture was stirred for at least 30 minutes. Succinimide O could beoptionally isolated by extraction with ethyl acetate, washing theorganic layer and solvent removed by distillation, or used directlywithout purification in the subsequent step. ¹H NMR (400 MHz, CDCl₃): δ5.83-5.74 (m, 1H), 5.12-4.99 (m, 2H), 4.13-3.99 (m, 1H), 2.81 (s, 4H),2.13-1.92 (m, 2H), 1.39-1.30 (m, 1H), 1.11-1.04 (m, 1H), 0.73-0.68 (m,1H).

Continuing through with crude succcinate intermediate O, tert-leucine(23.4 g, 1.25 eq) and K₃PO₄ (84.8 g, 2.8 eq.) were charged to thereactor. The resulting mixture was warmed to room temperature and theresulting solution was stirred for about 18 h. Upon reaction completion,the mixture was diluted by MTBE (210 mL) and pH adjusted to pH 3 with 6MHCl (˜180 mL). The layers were separated and the organic layer was pHadjusted to pH>10 with 2.5M NaOH (˜70 mL). The aqueous layer was removedand the organic layer was washed with 0.5 M NaOH (100 mL). The combinedbasic aqueous layers was readjusted to pH<3 with 6M HCl (˜50 mL) andwashed twice with MTBE (100 mL×2).

The combined organic layers were solvent swapped to MTBE (107 mL). In aseparate container, S(−) 1-phenylethylamine (10.9 g, 1 eq.) wasdissolved in MTBE (32.7 mL). The solution of the amine was chargedslowly to the solution containing the succinimide intermediate. A smallamount of VII (S)-1-phenylethan-1-amine salt (0.055 g, 0.5%) was chargedfollowed by the rest of the amine solution. The slurry was agedovernight to obtain a thick slurry. The resulting slurry was filteredand rinsed with MTBE (50 mL). The solids were dried in the vacuum ovenuntil constant weight was reached to obtain VII as the(S)-1-phenylethan-1-amine salt. NMRs of the free acid: ¹H NMR (400 MHz,CDCl₃) δ 7.4 (m, 5H), 6.3 (broad s, 3H), 5.8 (m, 1H), 5.3 (d, 1H), 5.1(d, 1H), 4.2 (q, 1H), 3.8 (d, 1H), 3.7 (m, 1H), 2.1 (m, 1H), 1.9 (m,1H), 1.5 (d, 3H), 1.1 (m, 1H), 0.9 (d, 9H), 0.8 (m, 1H), 0.5 (q, 1H).¹³C-NMR (CDCl₃) δ 173.1, 157.0, 115.7, 63.3, 53.9, 36.2, 34.9, 33.7,27.1, 17.3, 11.7.

D. Synthesis of(1R,2R)-1-Amino-2-(difluoromethyl)-N-((1-methylcyclopropyl)sulfonyl)cyclopropane-1-carboxamideHydrochloride Salt (XII)

The existing process route shown above was disclosed is in the U.S.Publication No. 2014-0017198. The route shown below proceeds through acommon known intermediate V-v. Racemic A-b was selectively hydrolyzed toracemic A-c with an approximate 10:1 ratio of cis/trans diastereomers.This mono acid is subjected to a classical resolution with a chiralamine to form chiral A-c as a salt. A recrystallization can be performedto enhance enantiomeric excess. The carboxylic acid was next convertedto the amide A-d and isolated. In telescoping steps, the amide wassubjected to a Hoffman rearrangement, hydrolysis to the amine,protection of the amine with Boc and hydrolysis of the methyl ester toform the desired amino acid, V-v. V-v was then converted to XII as shownin the above scheme.

Assembly Steps of Route I to Compound of Formula I

A. Synthesis of Compound of Formula III (R═CH₃)

I. Free-Basing and Boc-Protection of II (R═CH₃) to Provide III (R═CH₃):

II (10.1 g, 29.3 mmol, 1.00 equivalents) was combined withdichloromethane (40 mL) and the mixture stirred at about 20 to 25° C.Triethylamine (8.36 g, 82.6 mmol, 3.00 equivalents) was added dropwisevia syringe, maintaining a reaction temperature of about 20 to 25° C. Tothe resultant solution was charged 4-dimethylaminopyridine (360 mg, 2.95mmol, 0.1 equivalent) followed by a solution of di-tert-butyldicarbonate (6.52 g, 29.9 mmol, 1.02 equivalent) in dichloromethane (40mL), while maintaining a reaction temperature of about 20 to 25° C. Themixture was stirred for about 2-4 hours and monitored for completion.Upon reaction completion, 100 mL of 1.0 N HCl was charged dropwise,while maintaining a reaction temperature below about 30° C. The biphasicmixture was vigorously stirred for about 15 minutes followed by allowingthe layers to separate. The bottom organic layer was partitioned andwashed successively with 5% wt/wt aqueous sodium bicarbonate (100 mL)and water (100 mL). The organic phase was concentrated under reducedpressure and dried under vacuum to afford III (R═CH₃). ¹H NMR (300 MHz,CD₃OD): δ 4.41 (d, J=6.0 Hz, 1H), 4.01-4.07 (m, 1H), 3.65-3.79 (m, 4H),3.05-3.15 (m, 1H), 2.10-2.20 (m, 1H), 1.50-1.60 (m, 1H), 1.39-1.45 (appd, 9H), 1.10-1.20 (m, 2H), 0.99-1.08 (m, 3H). ¹³C NMR (75 MHz, CDCl₃): δ12.3, 21.3, 28.2, 50.5, 50.6, 51.4, 52.2, 61.8, 71.9, 80.2, 154.2,171.9.

B. Synthesis of Compound of Formula V (R═CH₃)

II. S_(N)Ar Reaction of IV with III (R═CH₃) to form V (R═CH₃)

Into a reactor containing III (R═CH₃) (1.00 equivalent) inN,N-dimethylacetamide (6 volumes) was charged IV (1.00 equivalent) andcesium carbonate (1.20 equivalents) under nitrogen atmosphere. Theheterogeneous reaction was heated to about 100 to 110° C. with stirring.Upon reaction completion, the reaction mixture was then cooled down toabout 20° C. and methyl tert-butyl ether (10 volumes) was charged. Theresulting mixture was washed twice with water (6 volumes) and the methyltert-butyl ether solvent was swapped with isopropanol (6 volumes) viavacuum distillation. The solution was then heated to about 60° C. andwater (3 volumes) slowly added over about 1.5 hours. Once the additionwas complete, the mixture was held at about 60° C. for about 30 minutes.A small amount of V (R═CH₃) (1-2 wt/wt %) were then charged after whichthe temperature was slowly cooled to room temperature over about 3hours. The contents were then aged for at least about 12 hours afterwhich the slurry was filtered over the appropriate filter. The wet cakewas washed with 2:1 isopropanol/water (3.5 volumes), followed by twowater washes (3.5 volumes) and oven dried under vacuum at about 40 to45° C. ¹H NMR (400 MHz, CDCl₃): δ 7.93-7.90 (m, 1H), 7.25-7.22 (m, 1H),7.20-7.16 (m, 1H), 5.95-5.85 (m, 1H), 5.44-5.38 (m, 1H), 5.25-5.21 (m,2H), 4.54-4.52 (m, 1H), 4.47-4.40 (m, 1H), 3.97 (s, 3H), 3.77 (s, 3H),3.43-3.39 (m, 1H), 3.27-3.17 (m, 2H), 2.79-2.68 (m, 1H), 1.64-1.55 (m,1H), 1.44-1.43 (m, 9H), 1.44-1.32 (m, 1H), 1.10-1.06 (m, 3H). LCMS(M+1): 521.97.

C. Synthesis of Compound of Formula VI (R═CH₃) Tosylate Salt

I. Boc Deprotection of V (R═CH₃) to Provide VI (R═CH₃)

V (R═CH₃) (50.0 g, 95.9 mmol, 1.00 equivalents) is combined with methyltetrahydrofuran (150 mL, 3 volumes) and the mixture was agitated atabout 15 to 25° C., preferably about 20° C. Para-toluenesulfonic acid(45.6 g, 240 mmol, 2.50 equivalents) in methyl tetrahydrofuran (100 mL,2 volumes) was charged to the reaction mixture. Once the acid additionwas complete, the contents were heated to about 50 to 60° C. thereaction contents were agitated for about 3 to 5 hours. Upon reactioncompletion, methyl tert-butyl ether (100 mL, 2 volumes) was added slowlyto the slurry. The contents were then cooled to about 15 to 25° C., andthe slurry was filtered and washed with a mixture of methyltetrahydrofuran (105 mL, 2.1×) and methyl tert-butyl ether (45 mL, 0.9volumes). The solids were placed in a vacuum oven to dry at about 35 to45° C. ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H), 9.58 (s, 1H), 7.92 (d,J=9.2 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.31-7.21 (m, 1H), 7.11 (t, J=5.7Hz, 3H), 5.97-5.77 (m, 1H), 5.49 (t, J=7.1 Hz, 1H), 5.19 (dd, J=27.6,13.7 Hz, 2H), 4.73 (dd, J=12.1, 5.7 Hz, 1H), 4.49 (dd, J=11.8, 6.4 Hz,1H), 3.93 (d, J=9.1 Hz, 3H), 3.77 (s, 3H), 3.60 (dd, J=13.2, 3.5 Hz,1H), 3.17 (td, J=16.8, 7.0 Hz, 2H), 2.84 (dd, J=14.1, 6.9 Hz, 1H), 2.30(s, 3H), 1.67-1.34 (m, 2H), 1.05 (t, J=7.4 Hz, 3H). LC/MS: M/Z=422.2.

D. Synthesis of Compound of Formula VIII (R═CH₃)

I. Salt Break of VII to Provide VII Free-Acid

VII (33.0 g, 87.6 mmol, 1.0 equivalents) was combined with methyltert-butyl ether (198 mL, 6 volumes) and the resulting suspension wasagitated. A solution of concentrated hydrochloric acid (33 mL, 1.0volume) and water (165 mL, 5 volumes) was charged to the suspension at arate that maintained a reaction temperature of about 15 to 25° C. As theacid was added, the suspension became a biphasic solution. The resultingreaction mixture was agitated for about 1 hour at about 15 to 25° C.Agitation was stopped and the layers separated for about 15 minutesbefore the aqueous layer was removed. Water (330 mL, 10 volumes) wasadded to the organic and was agitated for about 15 min at about 15 to25° C. Agitation was stopped and the layers separated for about 15minutes before the aqueous layer was removed. Water (330 mL, 10 volumes)was added to the organic and was agitated for about 15 min at about 15to 25° C. Agitation was stopped and the layers separated for about 15minutes before the aqueous layer was removed. A solution of 10 wt. %sodium chloride in water (300 mL, 9 volumes) was added to the organicand the mixture was agitated for about 15 min at about 15 to 25° C.Agitation was stopped and the layers were separated for about 15 minutesbefore the aqueous layer was removed. The resulting organic layer wasthen concentrated to the minimum volume and was diluted withdimethylformamide (297 mL, 9 volumes). The final solution was removedand polish filtered.

II. Amide Coupling of VI (R═CH₃) and VII to Provide VIII (R═CH₃)

VII (R═CH₃) (40.0 g; 67.4 mmol; 0.77 eq.), EDC.HCl (16.8 g, 87.6 mmol,1.0 eq.), and HOBt monohydrate (13.4 g, 87.6 mmol, 1.0 eq) were combinedin a reaction vessel. The previously prepared VII in DMF solution wascharged to the solids, rinsed forward with DMF (39.6 mL, 1.2 vol) andagitated to form a solution. The reaction mixture was cooled to about 0to 10° C. before NMM was charged (19.3 mL, 175 mmol, 2.0 eq.). Thecontents are agitated at about 0 to 10° C. for no less than about 1hour. The reaction mixture was then adjusted to about 15 to 25° C. andagitated until reaction was complete by LC analysis. Upon reactioncompletion, toluene (429 mL, 13 volumes) was charged to the reactor andthe temperature adjusted to about −5 to 5° C. Water (198 mL, 6 volumes)was slowly charged to maintain a reaction temperature between about 0and 25° C. After water addition was complete, the contents were adjustedto about 15 to 25° C. Agitation was stopped and the contents settled forno less than 15 minutes before the aqueous layer was removed. A solutionof potassium carbonate (20.6 g, 149 mmol, 1.7 equivalents) in water (181mL, 5.5 volumes) was charged to the organic phase and the resultingsolution permitted to and agitate for about 15 minutes before theagitation was stopped and the contents were allowed to settle for about15 minutes. The aqueous basic layer was removed. Water (181 mL, 5.5volumes) was charged to the organic phase and agitated for about 15minutes before the agitation was stopped and the contents allowed tosettle for about 15 minutes. The aqueous basic layer was removed. Theorganic phase was again partitioned between water (181 mL, 5.5 volumes)and agitated for about 15 minutes before agitation was stopped and thecontents allowed to settle for about 15 minutes. The aqueous basic layerwas removed. A solution of sodium chloride (20.5 g; 350 mmol 4.00equivalents) in water (181 mL; 5.5 volumes) was charged to the organicand agitated for about 15 minutes before agitation was stopped and thecontents settled for about 15 minutes. The aqueous acidic layer wasremoved. The organic was concentrated to minimum stirring volume and wasremoved and polish filtered.

¹H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.1 Hz, 1H), 7.19-7.34 (m, 3H),6.09-5.78 (m, 2H), 5.55-5.21 (m, 3H), 5.06 (dd, J=32.9, 13.4 Hz, 2H),4.92 (d, J=8.5 Hz, 1H), 4.59 (dd, J=10.7, 6.3 Hz, 1H), 4.35 (d, J=9.7Hz, 1H), 4.11-3.92 (s, 3H), 3.95-3.87 (m, 1H), 3.85 (d, J=28.1 Hz, 3H),3.78-3.70 (m, 1H), 3.37-3.17 (m, 2H), 2.81-2.69 (m, 1H), 2.18-2.06 (m,1H), 1.95 (d, J=7.4 Hz, 1H), 1.63 (dd, J=14.4, 7.3 Hz, 1H), 1.48 (dd,J=14.4, 7.2 Hz, 1H), 1.17 (t, J=7.4 Hz, 3H), 1.12 (s, 9H), 0.84 (s, 1H),0.54 (d, J=6.4 Hz, 1H). LC/MS: m/z=659.

E. Synthesis of Compound of Formula IX (R═CH₃)

Ring Closing Metathesis of VIII (R═CH₃) to Provide IX (R═CH₃):

VIII (R═CH₃) (33 g of a 14.3 wt. % solution in toluene, 7.1 mmol, 1.00equivalents) and toluene (27 mL) were combined and the mixture wasagitated and heated to reflux (110° C.) and held at reflux temperaturefor about 3 to 5 hours. Separately, toluene (20 mL) was charged to areaction vessel. and degassed vigorously. Zhan 1B catalyst (173 mg, 0.24mmol, 0.033 equivalents) was charged and the mixture is agitated atabout 20 to 25° C. for about 60 minutes to obtain a homogenous solution.The toluene solution of Zhan catalyst was added to the refluxing toluenesolution of VIII (R═CH₃) over about 2 hours, maintaining a reactiontemperature of about 111° C. Upon reaction completion, the reaction wascooled to about 20° C. and 9.4 grams (2S) of silica gel was charged. Theslurry was vigorously agitated for about 4 hours and then filtered. Thereactor and filter were washed with isopropyl acetate (2×32 mL) and thefiltrate was concentrated to 50% volume (approximately 11×). To thissolution was charged 2.4 grams of activated charcoal. The slurry wasvigorously agitated for about 4 hours and then filtered. The reactor andfilter were washed with isopropyl acetate (2×16 mL) and the filtrate wassolvent exchanged to 5 volumes of isopropyl acetate and used directlynext step. ¹H NMR (300 MHz, CDCl₃): δ 7.95 (d, J=6.0 Hz, 1H), 7.26 (m,1H), 7.12 (m, 1H), 5.89 (m, 1H), 5.69 (m, 2H), 5.22 (d, J=9.0 Hz, 1H),4.77 (d, J=6.0 Hz, 1H), 4.40 (d, J=9.0 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H),4.02-3.95 (m, 1H), 3.96 (s, 3H), 3.85 (m, 1H), 3.73 (s, 3H), 3.21 (s,2H), 2.90-2.70 (m, 1H), 2.49 (d, J=12.0 Hz, 1H), 1.41 (m, 2H), 1.25-1.18(m, 4H), 1.06 (s, 9H), 1.00-0.93 (m, 2H), 0.50 (m, 1H). LCMS:m/z=631.02.

In addition, other promoters (e.g., acetic acid, benzoquinones, CuI,CsCl, or Ti(O-i-Pr)₄), ethylene, or promoting conditions (e.g.,microwave irradiation) may be employed. Further, temperatures rangingfrom about 40° C. to 110° C. may be used. Other solvents, such ashalogenated (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene,or hexafluorobenzene), organic (e.g., benzene, THF, methyl-tert-butylether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethylcarbonate, dimethyl formamide, acetonitrile), or alcohols (e.g.,methanol, isopropanol) may be used.

F. Synthesis of Compound of Formula X (R=CHA)

Hydrogenation of IX (R═CH₃) to Provide X (R═CH₃):

IX (R═CH₃) in 5 volumes of iso-propyl acetate (IPAc) and Pt/C (5 wt %relative to IX (R═CH₃)) were charged to a reaction vessel. The reactorwas inerted with N₂, then evacuated and filled with H₂ to 5 psig. Themixture was stirred vigorously for about 12 to 24 hours under 5 psig H₂at room temperature. After completion of the reaction, diatomaceousearth (5 wt %) was charged, and mixture was filtered to remove thesolids, rinsing forward with additional IPAc. The IPAc solution wastreated with 6 volumes of 5% aqueous N-acetyl cysteine solution at about50° C. for overnight under N₂ with vigorous agitation. After cooling toroom temperature, the aqueous layer was removed and the organic layerwas rinse with 6 volumes of 5-10% aqueous NaHCO₃ and 6 volumes of 10%aqueous NaCl. Diatomaceous earth (0.5 S) was added, the mixture wasstirred for about 5 minutes, and the solids were subsequently removed byfiltration. The solution of X (R═CH₃) was carried on without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=9.2 Hz, 1H), 7.26 (dd, J=9.2, 2.7Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 5.88 (d, J=3.9 Hz, 1H), 5.29 (d, J=9.9Hz, 1H), 4.74 (d, J=7.2 Hz, 1H), 4.38-4.25 (m, 2H), 4.13-4.07 (m, 1H),3.94 (s, 3H), 3.78-3.76 (m, 1H), 3.71 (s, 3H) 2.63 (app dd, J=15.0, 7.5Hz, 1H), 2.54-2.32 (m, 1H), 2.02-1.98 (m, 1H), 1.84-1.63 (m, 4H),1.53-1.33 (m, 3H), 1.30-1.10 (m, 4H), 1.07 (s, 9H), 0.95-0.80 (m, 2H),0.77-0.64 (m, 1H), 0.46 (dd, J=12.9, 6.3 Hz, 1H). 19F NMR (376 MHz,CDCl3) δ −102.43 (ddd, J=250.4, 25.4, 8.6 Hz), −103.47 (ddd, J=250.4,28.7, 11.3 Hz).

F. Synthesis of Compound of Formula XI (R═H) from X (R═CH₃)

II. Hydrolysis of X to Provide XI:

To solution of X (R═CH₃) in IPA (7 volumes) at about 30° C. under N₂ wasadded a solution of aqueous LiOH over about 5 to 10 minutes (1M, 2.3eq). The reaction mixture was warmed to an internal temperature of about40° C., and stirred. After cooling to room temperature MTBE (8 volumes)was added. The resulting mixture was acidified to pH 3 with 1M HCl. Theaqueous layer is removed and the organic layer is rinsed twice with 10%aqueous NaCl. Diatomaceous earth is added (0.1 S), and the resultingslurry is filtered, rinsing forward with additional MTBE. The MTBE isremoved via vacuum distillation, and the resulting solids are dissolvedin 5 volumes of ethanol and 5 volumes of heptane at about 60 to 65° C.The solution is then cooled to about 45 to 50° C. and seeded with aslurry of XI in ethanol/heptane (0.005 S). After stirring for about 6hours at about 45° C., the slurry is cooled to about 15° C. over about10 hours. An additional volumes of heptane are added over about 1 hour.XI was isolated via vacuum filtration and rinsed with 5 volumes of 1:9EtOH:heptane. The resulting solids are dried in a vacuum oven at about40° C. to constant weight. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=9.2 Hz,1H), 7.24 (dd, J=9.2, 2.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 5.87 (d,J=3.5 Hz, 1H), 5.47 (d, J=9.9 Hz, 1H), 4.72 (d, J=7.2 Hz, 1H), 4.33 (d,J=12.2 Hz, 1H), 4.32 (d, J=9.9 Hz, 1H), 4.04 (dd, J=11.9, 4.0 Hz, 1H),3.93 (s, 3H), 3.7 (m, 1H), 2.64 (m, 1H), 2.43 (m, 1H), 1.99 (m, 1H),1.8-1.3 (m, 6H), 1.25-1.15 (m, 3H), 1.0 (m, 1H). ¹³C NMR (75 MHz,CDCl₃): δ 172.63, 171.64, 162.06, 157.49, 153.37, 142.42, 139.12 (dd,J_(CF)=30.6, 25.8 Hz), 133.06, 130.44, 120.1 (t, J_(CF)=245 Hz), 119.93,105.31, 77.45, 61.66, 59.49, 55.74, 54.98, 51.92, 46.52, 36.42 (t,J_(CF)=25.0), 34.91, 30.35, 27.74, 26.19, 21.53, 19.99, 18.34, 12.06,11.33.

G. Synthesis of Compound of Formula I from X (R═CH₃)

Synthesis of compound of formula I from X was similar to that describedin U.S. Publication No. 2014-0017198. X (R═CH₃) was hydrolyzed to formXI (R═H) which was coupled with XII to form I.

What is claimed is:
 1. A crystalline form of compound I:

wherein, the crystalline form is an ethanol solvate (Compound I Form I),characterized by an X-ray powder diffractogram comprising peaks (±0.2°)at 8.6, 11.1, and 15.5 °2θ as determined on a diffractometer using Cu-Kαradiation.
 2. Compound I Form I according to claim 1, wherein thediffractogram further comprises a peak at 12.9 °2θ±0.2°.
 3. Apharmaceutical composition comprising a Compound I Form I according toclaim 1, and a pharmaceutically acceptable excipient.
 4. A method fortreating a subject suffering from hepatitis C virus (HCV), comprisingadministering to the subject a therapeutically effective amount of aCompound I Form I according to claim 1 and a pharmaceutically acceptableexcipient.
 5. The method according to claim 4, comprising furtheradministering to the subject at least one anti-HCV agent.
 6. Compound IForm I according to claim 1, wherein the diffractogram is substantiallyas shown in FIG.
 1. 7. Compound I Form I according to claim 1,characterized by a differential scanning calorimetry (DSC) curvesubstantially as shown in FIG.
 2. 8. Compound I Form I according toclaim 1, characterized by a differential scanning calorimetry (DSC)curve that comprises an endotherm at about 149° C., an exotherm at about212° C., and an endotherm at about 275° C.
 9. Compound I Form Iaccording to claim 1, characterized by a thermogravimetric analysis(TGA) comprising a thermogram substantially as shown in FIG.
 3. 10.Compound I Form I according to claim 1, characterized by athermogravimetric analysis (TGA) with a weight loss of about 8.4% in atemperature range of about 30° C. to about 350° C.
 11. Compound I Form Iaccording to claim 1, characterized by a dynamic vapor sorption (DVS)curve substantially as shown in FIG.
 4. 12. New Compound I Form Iaccording to claim 1, characterized by a nuclear magnetic resonancespectrum (¹H NMR) substantially as shown in FIG.
 5. 13. Compound I FormI according to claim 1, further comprising about 1.7 mole equivalents ofethanol.